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Chondrocyte innate immune myeloid differentiation factor 88-dependent signaling drives procatabolic effects of the endogenous Toll-like receptor 2/Toll-like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice. Liu-Bryan Ru,Terkeltaub Robert Arthritis and rheumatism OBJECTIVE:Toll-like receptor 2 (TLR-2)/TLR-4-mediated innate immunity serves as a frontline antimicrobial host defense, but also modulates tissue remodeling and repair responses to endogenous ligands released during low-grade inflammation. We undertook the present study to assess whether the endogenous TLR-2/TLR-4 ligands low molecular weight hyaluronan (LMW-HA) and high mobility group box chromosomal protein 1 (HMGB-1), which are increased in osteoarthritic (OA) joints, drive procatabolic chondrocyte responses dependent on TLR-2 and TLR-4 signaling through the cytosolic adaptor myeloid differentiation factor 88 (MyD88). METHODS:We studied mature femoral head cap cartilage explants and immature primary knee articular chondrocytes from TLR-2/TLR-4-double-knockout, MyD88-knockout, and congenic wild-type mice. Generation of nitric oxide (NO), degradation of hyaluronan, release of HMGB-1, matrix metalloproteinase 3 (MMP-3), and MMP-13, and protein expression of type X collagen were assessed by Griess reaction and Western blotting analyses. Expression of messenger RNA for type II and type X collagen, MMP-13, and RUNX-2 was examined by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS:Interleukin-1beta and TLR-2 and TLR-4 ligands induced both HMGB-1 release from chondrocytes and extracellular LMW-HA generation in normal chondrocytes. TLR-2/TLR-4(-/-) and MyD88(-/-) mouse cartilage explants and chondrocytes lost the capacity to mount procatabolic responses to both LMW-HA and HMGB-1, demonstrated by >95% suppression of NO production (P < 0.01), and attenuated induction of MMP-3 and MMP-13. Combined deficiency of TLR-2/TLR-4, or of MyD88 alone, also attenuated release of NO and blunted induction of MMP-3 and MMP-13 release. MyD88 was necessary for HMGB-1 and hyaluronidase 2 (which generates LMW-HA) to induce chondrocyte hypertrophy, which is implicated in OA progression. CONCLUSION:MyD88-dependent TLR-2/TLR-4 signaling is essential for procatabolic responses to LMW-HA and HMGB-1, and MyD88 drives chondrocyte hypertrophy. Therefore, LMW-HA and HMGB-1 act as innate immune cytokine-like signals with the potential to modulate chondrocyte differentiation and function in OA progression. 10.1002/art.27475
Perioperative intravenous ketamine for acute postoperative pain in adults. The Cochrane database of systematic reviews BACKGROUND:Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting. OBJECTIVES:To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia. SEARCH METHODS:We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA:We sought randomised, double-blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non-steroidal anti-inflammatory drug (NSAID), with a basic analgesic alone. DATA COLLECTION AND ANALYSIS:Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS:We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S-ketamine and one only R-ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non-stratified analysis.Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate-quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate-quality evidence; 37 studies, 2449 participants).Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high-quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high-quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate-quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low-quality evidence; 23 studies, 1353 participants).Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small-study effects were present, or twice if numbers were small and small-study effects likely but testing not possible.Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate-quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI -11.9 to -2.2), compared with placebo (very low-quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small-study effects or because the number of participants was below 400.CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high-quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high-quality evidence; 95 studies, 5965 participants). AUTHORS' CONCLUSIONS:Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance. 10.1002/14651858.CD012033.pub4
Composite measure to assess efficacy/gastrointestinal tolerability of tapentadol ER versus oxycodone CR for chronic pain: pooled analysis of randomized studies. Merchant Sanjay,Provenzano David,Mody Samir,Ho Kai Fai,Etropolski Mila Journal of opioid management OBJECTIVE:To evaluate a composite measure for chronic pain that balances pain relief with tolerability. DESIGN:Post hoc meta-analysis of three randomized, multicenter, double-blind studies. PARTICIPANTS:Subjects with moderate-to-severe chronic osteoarthritis knee pain or low back pain who had been randomized to receive active treatment with tapentadol extended release (ER; n = 978) or oxycodone controlled release (CR; n = 999). Twenty-two subjects were excluded, mainly because they did not receive treatment. MAIN OUTCOME MEASURES:We defined the composite measure as ≥30 percent pain relief without nausea/vomiting/constipation and without discontinuations (≥30 percent PRT [pain relief/tolerability]). We also considered ≥50 percent PRT as well as ≥30 percent and ≥50 percent pain relief without any adverse events of any type. To further evaluate ≥30 percent PRT, we studied its relationship with four patient-reported outcomes: EQ-5D, Physical and Mental Component Summaries of SF-36, Patient Global Impression of Change, and Patient Assessment of Constipation Symptoms. RESULTS:At week 12, tapentadol ER recipients were more likely to have ≥30 percent PRT than oxycodone CR recipients (OR, 3.15; 95% CI, 2.47, 4.00; p < 0.001). Significant differences were also observed with the other three composite measures (p < 0.001). At week 12, subjects with ≥30 percent PRT had more favorable changes in all patient-reported outcomes than those without and were more likely to have threshold changes in EQ-5D and SF-36 (all p < 0.001). CONCLUSIONS:Tapentadol ER was associated with significantly better composite outcomes than oxycodone CR. Because both pain relief and gastrointestinal tolerability appeared to be related to outcomes, the composite measure may represent a useful tool for comparing opioids that merits further evaluation. 10.5055/jom.2013.0147
Benefits of weight loss of 10% or more in patients with overweight or obesity: A review. Obesity (Silver Spring, Md.) OBJECTIVE:Modest weight loss (5%-10%) is clinically meaningful in patients with overweight or obesity. However, greater weight loss may be required to achieve improvements in or remission of certain weight-related complications. Therefore, this study reviewed the effect of large weight loss (≥10%). Most studies reporting large weight loss and relevant outcomes used bariatric surgery or lifestyle modifications. RESULTS:Benefits of large weight loss were observed in patients with various overweight- or obesity-related complications, including improvements in comorbidities such as type 2 diabetes and hypertension. Improvements in glucose metabolism and cardiovascular risk factors were observed in patients who achieved large weight loss through lifestyle interventions or pharmacotherapy (phentermine/topiramate 15/92 mg once daily or subcutaneous semaglutide 2.4 mg once weekly). Other benefits associated with large weight loss included reduced cancer risk and improvements in knee osteoarthritis, sleep apnea, fertility-related end points, and health-related quality of life. While costly, bariatric surgery is currently the most cost-effective intervention, although most weight-management programs are deemed cost-effective. CONCLUSIONS:Overall, large weight loss has a major beneficial impact on overweight- and obesity-related complications. Large weight loss should be the main treatment target when modest weight loss has had insufficient effects on obesity-related complications and for patients with severe obesity. 10.1002/oby.23371
Pregnancy-induced changes in rabbit medial collateral ligament vasoregulation. McDougall J J,Giles R W,Bray R C,Hart D A The American journal of physiology The ligaments of weight-bearing joints are known to become mechanically inferior during pregnancy, and it has been postulated that this may be due to changes in tissue perfusion. Calcitonin gene-related peptide (CGRP) and epinephrine exert a tonic influence on the vasculature of the medial collateral ligament (MCL), and the present study examined whether these vasoactive influences were altered by pregnancy. Ligament perfusion experiments were performed on primigravid New Zealand White rabbits with the use of laser Doppler perfusion imaging. In pregnant animals (day 29), MCL basal perfusion fell significantly compared with control; however, values returned to normal 5 days postpartum. In normal joints, topical application of CGRP resulted in a dose-dependent increase in MCL perfusion, whereas epinephrine administration caused a dose-dependent fall in blood flow. During pregnancy, the vasodilator effect of CGRP was completely abolished, whereas adrenergic vasoconstriction was greater than normal. Both responses returned postpartum. Pregnancy in the rabbit produces hypoemia in the MCL, and this phenomenon may be effected by a tempering of CGRP dilator responses and an augmentation of alpha-adrenoceptor-mediated vasoconstriction. 10.1152/ajpregu.1998.275.4.R1380
The role of IFN regulatory factor-1 in synovitis and nitric oxide production. Shiraishi A,Dudler J,Lotz M Journal of immunology (Baltimore, Md. : 1950) The IFN regulatory factor-1 (IRF-1) DNA binding protein regulates expression of genes that are involved with the induction of immune and inflammatory responses. The present study used mice with a targeted disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to examine the role of this transcription factor in synovial inflammation and nitric oxide production. Intraarticular injection of IL-1 or LPS was associated with a significantly reduced intensity of synovial lining hyperplasia and leukocyte infiltration in the IRF-1-/- mice as compared with wild-type mice of the same parental lineage C57BL/6. Nitric oxide (NO) is involved with the pathogenesis of arthritis, and IRF-1 regulates expression of inducible NO synthase (iNOS) in mononuclear phagocytes. Articular chondrocytes from IRF-1-/- mice produced similar levels of NO in response to IL-1 or LPS. Furthermore, the synergistic induction of NO by IFN-gamma and IL-1 or LPS was almost identical in chondrocytes from wild-type and IRF-1-/- mice. This was in contrast to the expected decrease in NO production by peritoneal macrophages from IRF-1-/- mice, suggesting that IRF-1 is not required for iNOS expression in chondrocytes. These results indicate that IRF-1 has a tissue-specific role in the induction of iNOS. Inhibition of this transcription factor may represent a novel approach in controlling inflammatory diseases such as arthritis.
Acupotomy Improves Synovial Hypoxia, Synovitis and Angiogenesis in KOA Rabbits. Journal of pain research Purpose:Knee osteoarthritis (KOA) is a chronic inflammatory disease highly associated with intra-articular hypertension, hypoxia and angiogenesis of synovial tissue. Our previous studies showed that acupotomy could treat KOA in a variety of ways, including reducing cartilage deterioration and enhancing biomechanical qualities. However, the mechanism of hypoxia and angiogenesis induced by acupotomy in KOA synovium remains unclear. This study looked for the benign intervention of acupotomy in synovial pathology. Methods:The rabbits were divided into 3 groups, Normal group, KOA group, and KOA + Acupotomy (Apo) group, with 11 rabbits in each group. The KOA rabbit model was established by the modified Videman method with six weeks. The KOA + Apo group performed the intervention. The tendon insertion of vastus medialis, vastus lateralis, rectus femoris, biceps femoris, and anserine bursa were selected as treatment points in rabbits. Rabbits were treated once every 7 days for 3 weeks. We observed the intra-articular pressure and oxygen partial pressure (BOLD MRI). The synovial morphology was monitored by Hematoxylin-Eosin Staining (HE Staining). The expression of hypoxia-inducible transcription factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) was detected using Immunohistochemical (IHC), Western Blot and Enzyme-Linked Immunosorbent Assay (ELISA). Results:Acupotomy reduced intra-articular hypertension and improved the synovial oxygen situation, synovial inflammatory and angiogenesis. HIF-1α, VEGF, IL-1β and TNF-α expression were downregulated by acupotomy. Conclusion:Acupotomy may reduce inflammation and angiogenesis in KOA rabbit by reducing abnormally elevated intra-articular pressure and improving synovial oxygen environment. The above may provide a new theoretical foundation for acupotomy treatment of KOA. 10.2147/JPR.S396955
The receptors and role of angiotensin II in knee joint blood flow regulation and role of nitric oxide in modulation of their function. Najafipour H,Ketabchi F Microcirculation (New York, N.Y. : 1994) OBJECTIVES:Angiotensin-converting enzyme (ACE) upregulation in the stroma cells of arthritis rheumatoid joints may produce a higher tissue concentration of angiotensin II (angII), which is a vasoconstrictor and mitogen factor that causes local hypoxia and synovial proliferation. No study in the literature has examined the role of angII in joint blood flow (JBF) regulation and the potential effect of ACE inhibitors on JBF. METHODS:The study was performed on 20 Dutch white rabbits to examine the JBF response to angII, angII receptor subtypes, and the role of nitric oxide (NO) in angII effects in knee joint blood vessels. Drugs were administered locally through retrograde saphenous artery cannulation. Joint vascular resistance (JVR) was calculated by dividing the arterial blood pressure by the JBF. RESULTS:AngII increased JVR dose dependently. The angII type 1 (AT(1)) receptor antagonist losartan did not change the basal JVR but completely blocked the effect of angII on JVR. N(omega)-nitro-L-arginin methyl ester (L-NAME) increased JVR by a mean (+/-SEM) of 25.8 +/- 8.7% (p < 0.05) but did not affect the joint vessel response to angII and losartan. CONCLUSIONS:AngII receptors are from the AT(1) subtype in normal joint blood vessels, but angII plays no significant role in JBF regulation. The basal release of NO plays a role in resting JBF regulation, but NO does not affect the AT(1) receptor-mediated vasoconstriction of joint blood vessels. 10.1038/sj.mn.7800205
Efficacy of Radiofrequency as Therapy and Diagnostic Support in the Management of Musculoskeletal Pain: A Systematic Review and Meta-Analysis. Diagnostics (Basel, Switzerland) Radiofrequency (RF) is a minimally invasive procedure used to interrupt or alter nociceptive pathways for treating musculoskeletal pain. It seems a useful tool to relieve chronic pain syndromes, even if, to date, solid evidence is still needed about the effectiveness of this therapy. By this systematic review and meta-analysis, we aimed to evaluate the efficacy of RF in treating musculoskeletal pain. PubMed, Medline, Cochrane, and PEDro databases were searched to identify randomized controlled trials (RCTs) presenting the following: patients with chronic musculoskeletal pain as participants; RF as intervention; placebo, anesthetic injection, corticosteroid injection, prolotherapy, conservative treatment, physiotherapy, and transcutaneous electrical nerve stimulation as comparisons; and pain and functioning as outcomes. Continuous random-effect models with standardized mean difference (SMD) were used to compare the clinical outcomes. Overall, 26 RCTs were eligible and included in the systematic review. All of them analyzed the efficacy of RF in four different regions: cervical and lumbar spine, knee, sacroiliac (SI) joint, shoulder. The outcomes measures were pain, disability, and quality of life. A medium and large effect in favor of the RF treatment group (SMD < 0) was found for the shoulder according to the Visual Analogical Scale and for the SI joint according to the Oswestry Disability Index. A small effect in favor of the RF treatment group (SMD > 0) was found for the spine according to the 36-item Short Form Survey. Non-significant SMD was found for the other outcomes. RF represents a promising therapy for the treatment of chronic musculoskeletal pain, especially when other approaches are ineffective or not practicable. Further studies are warranted to better deepen the effectiveness of RF for pain and joint function for each anatomical region of common application. 10.3390/diagnostics12030600
Acupuncture analgesia: II. Clinical considerations. Wang Shu-Ming,Kain Zeev N,White Paul F Anesthesia and analgesia BACKGROUND:Acupuncture and related percutaneous neuromodulation therapies can be used to treat patients with both acute and chronic pain. In this review, we critically examined peer-reviewed clinical studies evaluating the analgesic properties of acupuncture modalities. METHODS:Using Ovid and published medical databases, we examined prospective, randomized, sham-controlled clinical investigations involving the use of acupuncture and related forms of acustimulation for the management of pain. Case reports, case series, and cohort studies were not included in this analysis. RESULTS:Peer-reviewed literature suggests that acupuncture and other forms of acustimulation are effective in the short-term management of low back pain, neck pain, and osteoarthritis involving the knee. However, the literature also suggests that short-term treatment with acupuncture does not result in long-term benefits. Data regarding the efficacy of acupuncture for dental pain, colonoscopy pain, and intraoperative analgesia are inconclusive. Studies describing the use of acupuncture during labor suggest that it may be useful during the early stages, but not throughout the entire course of labor. Finally, the effects of acupuncture on postoperative pain are inconclusive and are dependent on the timing of the intervention and the patient's level of consciousness. CONCLUSIONS:Current data regarding the clinical efficacy of acupuncture and related techniques suggest that the benefits are short-lasting. There remains a need for well designed, sham-controlled clinical trials to evaluate the effect of these modalities on clinically relevant outcome measures such as resumption of daily normal activities when used in the management of acute and chronic pain syndromes. 10.1213/ane.0b013e318160644d
Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. Andrew D,Greenspan J D Journal of neurophysiology Tissue injuries commonly cause an increase in pain sensitivity, so that normally painful stimuli become more painful (hyperalgesia), and those usually associated with nonnoxious sensations evoke pain (allodynia). The neural bases for these sensory phenomena have been explored most extensively using heat injuries and experimental arthritis as models. Heat sensitization of cutaneous nociceptors is observed after burns, and sensitization of articular afferents to limb movements occurs after knee joint inflammation. These are likely to be peripheral mechanisms of hyperalgesia. Others, using different models of peripheral inflammation, have only rarely found mechanical sensitization of cutaneous nociceptors. In general these studies have failed to evaluate suprathreshold mechanical sensitivity, which has led to the concept of enhanced spinal cord processing ("central sensitization") serving as the neural substrate for mechanical hyperalgesia. In the current experiments, the mechanical and heat responses of cutaneous nociceptors supplying the glabrous skin of the rat hindpaw were studied 16-24 h after induction of acute inflammation with complete Freund's adjuvant. Single-fiber recordings were made from nociceptors in the sciatic nerve of barbiturate-anesthetized animals, and their responses compared with those obtained from nociceptors tested identically in normal animals. Nociceptors were characterized by the following: 1) graded mechanical stimuli (5-90 g) delivered with probes of tip area of 1 and 0.1 mm(2), 2) their adaptive responses to 2-min mechanical stimuli at three intensities, and 3) their responses to graded heat stimuli (40-50 degrees C). Forty-three nociceptors were studied in the inflamed state; 20 were A fibers, and the remainder were C fibers. Mechanical thresholds, determined with calibrated monofilaments, were not significantly different from controls. Sensitization to suprathreshold mechanical stimuli was observed for both A- and C-fiber nociceptors, although it was greater for the A fibers. Similarly, sensitization during testing of adaptive properties of A- and C-fiber nociceptors was seen, although it was limited to the dynamic (initial) and not the static (plateau) phase of the response. Heat sensitization was observed in 25% of A-fiber nociceptors, but the responses of C fibers to heat were depressed. Other indicators of neuronal sensitization, such as spontaneous activity and expanded receptive fields, were also observed. It was concluded that the mechanical hyperalgesia caused by peripheral inflammation could be explained by nociceptor sensitization. Central mechanisms cannot be completely ruled out as contributing to such hyperalgesia, although their role may be much smaller than previously envisaged. 10.1152/jn.1999.82.5.2649
The Analgesic Effect of Transcranial Direct Current Stimulation (tDCS) combined with Physical Therapy on Common Musculoskeletal Conditions: A Systematic Review and Meta-Analysis. Principles and practice of clinical research (2015) BACKGROUND:The analgesic effects of transcranial Direct Current Stimulation (tDCS) combined with physical therapy remain unclear. OBJECTIVE:To systematically review available evidence comparing tDCS with any physical therapy modality (PTM) to PTM alone or PTM with sham tDCS on pain relief on common musculoskeletal (MSK) conditions, namely knee osteoarthritis (KOA), chronic low back pain (CLBP), myofascial pain syndrome (MPS) and fibromyalgia. METHODS:EMBASE and MEDLINE were searched from inception to April 2019 for randomized controlled trials. Reviewers independently assessed the studies quality and extracted data according to the PRISMA protocol. The GRADE approach was used to asses quality of evidence and a "Summary of Findings" table was created. The analyses used random-effects model. The primary outcome was pain reduction after treatment. RESULTS:Eight articles were included. Only one study had low risk of bias. Quality of evidence was considered low or very low. Significant reduction in pain scores were found for fibromyalgia and KOA (Standardized mean difference (SMD) = -1.94 [95% CI: -3.37 to -0.49; =76.4%] and SMD = -2.35 [95% CI: -3.63 to -1.06; =69.7%] respectively). Subgroup analysis considering the type of PTM despite MSK condition revealed significant reduction in pain scores for exercise, SMD = -1.20 [95% CI: -1.683 to -0.717; =10.8%]. CONCLUSIONS:Large heterogeneity and low quality of evidence and limited number of studies were found. Results suggest a potential analgesic effect of tDCS in combination with a PTM for fibromyalgia and KOA. Subgroup analysis suggests a stronger effect of tDCS when combined with an exercise based PTM. 10.21801/ppcrj.2020.61.5
Botulinum toxin treatment of pain syndromes -an evidence based review. Safarpour Yasaman,Jabbari Bahman Toxicon : official journal of the International Society on Toxinology This review evaluates the existing level of evidence for efficacy of BoNTs in different pain syndromes using the recommended efficacy criteria from the Assessment and Therapeutic Subcommittee of the American Academy of Neurology. There is a level A evidence (effective) for BoNT therapy in post-herpetic neuralgia, trigeminal neuralgia, and posttraumatic neuralgia. There is a level B evidence (probably effective) for diabetic neuropathy, plantar fasciitis, piriformis syndrome, pain associated with total knee arthroplasty, male pelvic pain syndrome, chronic low back pain, male pelvic pain, and neuropathic pain secondary to traumatic spinal cord injury. BoNTs are possibly effective (Level C -one class II study) for female pelvic pain, painful knee osteoarthritis, post-operative pain in children with cerebral palsy after adductor release surgery, anterior knee pain with vastus lateralis imbalance. There is a level B evidence (one class I study) that BoNT treatment is probably ineffective in carpal tunnel syndrome. For myofascial pain syndrome, the level of evidence is U (undetermined) due to contradicting results. More high quality (Class I) studies and studies with different types of BoNTs are needed for better understanding of the role of BoNTs in pain syndromes. 10.1016/j.toxicon.2018.01.017
Comparison of Cytotoxic Effects of Intra-Articular Use of Tranexamic Acid versus Epinephrine on Rat Cartilage. Sukur Erhan,Kucukdurmaz Fatih Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Adequate visualization is known to be essential to perform arthroscopic procedures effectively and efficiently. We hypothesized that tranexamic acid may be considered as an alternative agent to reduce intra-articular bleeding during arthroscopic procedures, after comparing its potential chondrotoxicity with that of epinephrine. MATERIAL AND METHODS Seventy-two rats were randomized into 3 groups with 24 rats each. The injections were performed in the right knees, as follows: Group 1: 0.25 mL of tranexamic acid solution, Group 2: 0.25 mL of epinephrine solution, and Group 3: 0.25 mL of 0.9% saline, serving as control. One week after the injections, the animals were euthanized. Samples were evaluated histologically based on the Osteoarthritis Research Society International (OARSI) Histopathology Grading and Staging System and the "live/dead" staining technique to determine chondrocyte viability. RESULTS Comparison of epinephrine and tranexamic acid revealed significantly higher OARSI scores in the epinephrine group (epinephrine: 3.42±1.31, TA: 0.92±0.90; P<0.001). The most significant difference between the 2 groups was in the number of joints diagnosed with OARSI grade III. The percentage of viability was significantly higher in the tranexamic acid group when compared with the epinephrine group (tranexamic acid: 79.74±3.343; epinephrine: 63.81±1.914; P<0.05). CONCLUSIONS Based on the histologic parameters and chondrocyte viability, tranexamic acid is less cytotoxic than epinephrine in rat chondrocytes at the doses typically used in irrigation fluid, and may be a good alternative to epinephrine in arthroscopic surgery. 10.12659/msm.908560
A critical overview of the current myofascial pain literature - October 2015. Dommerholt Jan,Grieve Rob,Hooks Todd,Layton Michelle Journal of bodywork and movement therapies The number of publications about myofascial pain and trigger points (TrP) seems to increase every year. In the current overview we include 27 articles published in past months. The Basic Review section includes articles about the presence and characteristics of TrPs in various neck and shoulder muscles, the correlation between referred pain from active TrPs and knee osteoarthritis, and an anatomical study exploring whether the location of TrPs may be related to the nerve innervation of muscles. Zuil-Escobar and colleagues from Spain considered the intra-rater reliability of the identification of latent TrPs in several leg muscles and the possible correlation of TrP and the presence of a lower medial longitudinal arch. In the section on manual approaches, contributing author Rob Grieve and colleagues continue their studies of TrPs in the lower extremity muscles, while Méndez-Rebolledo and colleagues studied the impact of cross taping and compression. Dry needling (DN) continues to be a topic of interest. We included twelve papers addressing a wide range of topics, such as the effectiveness and safety of DN, and the impact of DN on proprioception, spasticity, and fibromyalgia. Two papers investigated the utilization of repetitive transcranial magnetic stimulation and laser on TrPs, The final section on other clinical studies and reviews includes 8 papers. The studies originated in thirteen different countries with Spain leading the charts with 7 contributions to the literature, followed by Brazil with four. As we have mentioned in previous editions of this literature overview, many studies suffer from very small sample sizes, which makes it difficult to reach definitive conclusions. Nevertheless, myofascial pain continues to be a topic of interest to researchers and clinicians around the globe. 10.1016/j.jbmt.2015.09.003
Elevated substance P and accelerated cartilage degradation in rabbit knees injected with interleukin-1 and tumor necrosis factor. O'Byrne E M,Blancuzzi V,Wilson D E,Wong M,Jeng A Y Arthritis and rheumatism Cytokines, interleukin-1 (IL-1), tumor necrosis factor alpha, and the neurotransmitter, substance P, have been implicated in the pathogenesis of arthritis because they stimulate synovial cells to secrete prostaglandin E2 and collagenase in vitro. We investigated in vivo changes in intraarticular substance P and the degradation of cartilage proteoglycan in response to intraarticular cytokine injections in rabbits. Twenty-four hours after a single injection of 10 ng, 30 ng, or 100 ng of recombinant human IL-1 alpha (rHuIL-1 alpha) per joint, the mean +/- SEM levels of substance P detected in the cell-free joint lavage fluid were 250 +/- 67 fmoles, 480 +/- 60 fmoles, and 530 +/- 130 fmoles (n = 4-5), respectively. The level of substance P in the contralateral knees injected with diluent was 58 +/- 8 fmoles (n = 12). The level of substance P had increased by 2 hours after IL-1 injection and remained elevated in the joint 48 hours after injection. Cytokine-induced proteoglycan depletion was also time- and dose-dependent. Proteoglycan concentrations in articular cartilage dissected from the weight-bearing condyles were calculated as the ratio of sulfated glycosaminoglycan measured using 1,9-dimethylmethylene blue: hydroxyproline. After 48 hours, 10 ng, 30 ng, or 100 ng of rHuIL-1 alpha per joint decreased proteoglycan levels by 9 +/- 4%, 14 +/- 4%, and 21 +/- 3% (n = 8), respectively. Likewise, the injection of recombinant human tumor necrosis factor alpha induced depletion of intraarticular substance P and cartilage proteoglycan. 10.1002/art.1780330715
Development of a Clinical Prediction Rule for Treatment Success with Transcranial Direct Current Stimulation for Knee Osteoarthritis Pain: A Secondary Analysis of a Double-Blind Randomized Controlled Trial. Biomedicines The study’s objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities’ Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant (p < 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66−56.69) and an 85% (95%CI: 60−96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets. 10.3390/biomedicines11010004
Evoked Release of Amino Acids and Prostanoids in Spinal Cords of Anesthetized Rats: Changes During Peripheral Inflammation and Hyperalgesia. Sorkin Linda S.,Moore John H. American journal of therapeutics C-fiber stimulation of the sciatic nerve in rats with an acute experimental arthritis elicited a greatly enhanced spinal release of several amino acids and prostaglandin PGE(2) (PGE(2)) when compared to control rats. The most dramatic change was in aspartate (Asp) which was not released in the control state but did increase significantly for a period outlasting the stimulation in the animals with knee joint inflammation. Evoked release of Glu, Gly, and PGE(2) also increased in the experimental group. It is proposed that the Asp acts primarily at N-methyl-D-asparate (NMDA) receptors to participate in the generation of hyperalgesia. In a similar model, direct activation of the NMDA receptors evoked spinal release of the same amino acids, including citrulline (an index of nitric oxide production) as well as representative prostanoids. Pretreatment with a NO synthase inhibitor blocked the release of Cit and Glu and reduced PGE(2) release evoked by NMDA, indicating that 1) Glu release is downstream of the actions of NO, and 2) the cyclooxygenase system is not independent of NO production. Evoked release of thromboxane B(2) was not affected by pretreatment with the nitric oxide synthesis inhibitor. Pretreatment with a cyclooxygenase inhibitor antagonized release of both prostanoids, but had little effect on NMDA-evoked increases in amino acids and Cit. 10.1097/00045391-199604000-00003
Transcranial direct current stimulation combined with peripheral stimulation in chronic pain: a systematic review and meta-analysis. Expert review of medical devices INTRODUCTION:The combination of Transcranial Direct Current Stimulation (tDCS) with peripheral stimulation may optimize their effects and bring positive results in treatment of people with chronic pain. AREAS COVERED:A systematic review with meta-analysis of randomized and non-randomized trials was performed to investigate the combination of tDCS with peripheral stimulation in adults with chronic pain. The primary outcome was pain intensity. Six studies were included in this review (sample of 228 participants), which investigated the combination of tDCS and transcutaneous electrical nerve stimulation, peripheral electrical stimulation, breathing-controlled electrical stimulation and intramuscular electrical stimulation. The conditions studied were knee osteoarthritis, spinal cord injury, chronic low back pain, and neurogenic pain of the arms. Pain intensity, measured by visual analog scale or numerical rating scale, was reduced in all included studies when at least one of the interventions was active, regardless they were combined or alone, with or without tDCS. However, meta-analysis showed superiority of tDCS used in combination with peripheral stimulation. EXPERT OPINION:This systematic review and meta-analysis suggests positive effects of tDCS combined with peripheral stimulation in chronic pain conditions. However, the evidence of the primary outcome was classified as low quality due to the limited number of studies. 10.1080/17434440.2022.2039623
Analgesic Effects of Interferential Current Therapy: A Narrative Review. Rampazo Érika Patrícia,Liebano Richard Eloin Medicina (Kaunas, Lithuania) : Transcutaneous electrical stimulation of low- and medium-frequency currents is commonly used in pain management. Interferential current (IFC) therapy, a medium frequency alternating current therapy that reportedly reduces skin impedance, can reach deeper tissues. IFC therapy can provide several different treatment possibilities by adjusting its parameters (carrier frequency, amplitudemodulated frequency, sweep frequency, sweep mode or swing pattern, type of application (bipolar or quadripolar), time of application and intensity). The objective of this review article is to discuss the literature findings on the analgesic efficacy of IFC therapy. : According to the literature, IFC therapy shows significant analgesic effects in patients with neck pain, low back pain, knee osteoarthritis and post-operative knee pain. Most of the IFC parameters seem not to influence its analgesic effects. We encourage further studies to investigate the mechanism of action of IFC therapy. 10.3390/medicina58010141
Interventions for osteoarthritis pain: A systematic review with network meta-analysis of existing Cochrane reviews. Osteoarthritis and cartilage open Objective:To conduct a network meta-analysis comparing all treatments for osteoarthritis (OA) pain in the Cochrane Library. Design:The Cochrane Library and Epistemonikos were searched for randomized controlled trials (RCTs) about treatments for hip and knee OA. We constructed 17 broad categories, comprising drug treatments, exercise, surgery, herbs, orthotics, passive treatments, regenerative medicine, diet/weight loss, combined treatments, and controls. In addition to a full network analysis, we compared the direct/indirect effects, and studies with shorter-/longer follow-up. CINeMA software was used for assessing confidence in network meta-analysis estimates. Results:We included 35 systematic reviews including 445 RCTs. There were 153 treatments for OA. In total, 491 comparisons were related to knee OA, less on hip OA, and only nine on hand OA. Six treatment categories showed clinically significant effects favoring treatment over control on pain. "Diet/weight loss" and "Surgery" had effect sizes close to zero. The network as a whole was not coherent. Of 136 treatment comparisons, none were rated as high confidence, six as moderate, 13 as low, and 117 as very low. Conclusions:Direct comparison of different available treatment options for OA is desirable, however not currently feasible in practice, due to heterogeneous study populations and lack of clear descriptions of control interventions. We found that many treatments were effective, but since the network as a whole was not coherent and lacked high confidence in the treatment comparisons, we could not produce a ranking of effects. 10.1016/j.ocarto.2022.100242
Intraarticular STP Radiofrequency for Painful Osteoarthritis in the Knee: A Retrospective Single Center Analysis. Journal of pain research OBJECTIVE:Osteoarthritis (OA) is the most common cause of chronic knee pain, often a debilitating condition that can cause a significant reduction in functional capacity. Radiofrequency is a form of neuromodulation that modulates pain signal transmission and has become progressively more common as a treatment for knee pain. This retrospective study aims to evaluate the efficacy of intraarticular radiofrequency in patients with chronic knee OA pain. MATERIALS AND METHODS:In this retrospective study, we included 129 patients undergoing intraarticular pulsed radiofrequency using the Poisson curve for energy distribution (Sluijter-Teixeira Poisson radiofrequency) (STP) from March 2018 to November 2019. Knee osteoarthritis severity was assessed prior to the procedure using the Lequesne Index, classifying patients into six groups based on level of severity. Pain intensity was assessed through a 10-cm visual analog scale (VAS), and level of patient satisfaction was assessed through a questionnaire. RESULTS:In the sample, pain reduction as measured by VAS compared to baseline prior to the procedure was statistically significant immediately following the procedure, at 30 days and at 90 days (p<0.001); this difference was less significant at 180 days (p<0.005). Efficacy in patients with moderate to severe disability was considerably greater than in patients with very severe to extremely severe disability. 57.36% reported that they were very satisfied, 29.46% satisfied, 9.3% neither satisfied nor dissatisfied, 2.33% dissatisfied, and 1.55% very dissatisfied. CONCLUSION:Our results suggest that STP radiofrequency may be a safe and effective procedure for knee OA, able to significantly reduce VAS scores at 1 month and 3 months compared to baseline. Based on our results, a key factor to consider when treating knee OA with STP radiofrequency is that it is more effective among patients with a lower level of disability. Due to the retrospective observational study design, prospective longitudinal investigation is required to further support the recommendation of STP radiofrequency for knee OA. 10.2147/JPR.S317569
Comparison of synovial PO2 and sympathetic vasoconstrictor responses in normal and acutely inflamed rabbit knee joints. Najafipour H,Ferrell W R Experimental physiology Experiments were performed to assess the effect of acute inflammation of the rabbit knee joint on the partial pressure of oxygen in synovial fluid (Ps,O2) and nerve-mediated vasoconstrictor responses of articular blood vessels. With the hypodermic needle oxygen electrode sited within the synovial cavity in the posterior region of the knee joint, mean (+/- S.E.M.). Ps,O2 was 37.4 +/- 3.6 mmHg (n = 10) in the inflamed group, which differed significantly (P < 0.05) from that occurring in the normal group from a different series (48.2 +/- 3.1 mmHg; n = 18). Ps,O2 was found to decrease with increasing depth of penetration of the oxygen electrode into the joint cavity of the inflamed knee, as in the normal knee. The lowest values were observed close to articular cartilage. Absolute blood flow was measured using radiolabelled microspheres whilst relative changes in blood flow were assessed using laser Doppler flowmetry. The former technique showed that the inflamed joints had a significantly higher blood flow. Electrical stimulation of the posterior articular nerve (PAN) of the knee resulted in vasoconstriction of knee joint blood vessels, which was accompanied by a reduction in Ps,O2. The frequency-response and voltage-response profiles to electrical stimulation of the PAN, although differing in magnitude, showed a high degree of correlation between blood flow and Ps,O2. The frequency-response profile to electrical stimulation of the PAN shifted to the right in inflamed joints compared with normal joints, suggesting a reduction in the efficacy of the sympathetic nervous system in regulating blood flow to the inflamed joints. Although the inflamed joint had a higher blood flow, Ps,O2 was lower compared with the normal joint. The results of this study show significantly altered blood flow, Ps,O2 and nerve-mediated constrictor responses in the acutely inflamed joint. These are related to the inflammatory response and may contribute to the pathogenesis of arthritis. 10.1113/expphysiol.1995.sp003841
Longitudinal effect of transcranial direct current stimulation on knee osteoarthritis patients measured by functional infrared spectroscopy: a pilot study. Neurophotonics Knee osteoarthritis (OA) is a common joint disease causing chronic pain and functional alterations (stiffness and swelling) in the elderly population. OA is currently treated pharmacologically with analgesics, although neuromodulation via transcranial direct current stimulation (tDCS) has recently generated a growing interest as a safe side-effect free treatment alternative or a complement to medications for chronic pain conditions. Although a number of studies have shown that tDCS has a beneficial effect on behavioral measures of pain, the mechanistic action of neuromodulation on pain sensitivity and coping at the central nervous system is not well understood. We aimed at observing longitudinal changes of cortical hemodynamics in older adults with knee OA associated with a two-week-long tDCS self-treatment protocol. Hemodynamics was measured bilaterally in the motor and somatosensory cortices with functional near-infrared spectroscopy (fNIRS) in response to thermal pain induced ipsilaterally to the knee primarily affected by OA. We found that both oxyhemoglobin- and deoxyhemoglobin-related functional activations significantly increased during the course of the tDCS treatment, supporting the notion that tDCS yields an increased cortical excitability. Concurrently, clinical measures of pain decreased with tDCS treatment, hinting at a potential spatial dissociation between cortically mediated pain perception and suppression and the prevalence of neuromodulatory effects over cortical pain processing. fNIRS is a valid method for objectively tracking pain in an ambulatory setting and it could potentially be used to inform strategies for optimized tDCS treatment and to develop innovative tDCS protocols. 10.1117/1.NPh.7.2.025004
Portable Transcutaneous Electrical Nerve Stimulation Therapy at Different Frequencies in the Treatment of Knee Osteoarthritis: A Quasi-Experimental Study. Charles Ang Poh Thean,Shukrimi Bin Awang,Zamzuri Bin Zakaria,Ardilla Hanim Binti Abdul Razak Journal of orthopaedic case reports Introduction:The prevalence of knee osteoarthritis is on the raise. This raise has been a huge financial burden to developed countries in treating the disease. Transcutaneous electrical nerve stimulation (TENS) is a cost-effective, easily available, and self-applicable mode of non-pharmacological pain relieve technique. Despite these advantages, the use, settings, and effectiveness of portable TENS are still poorly understood. The aim of this study is to determine the effectiveness of portable TENS at different frequencies in treating knee osteoarthritis. Materials and Methods:This is a single-center quasi-experimental study involving 100 patients seen in the outpatient department with knee osteoarthritis. They were randomly (computer generated) allocated into two arms (high frequency [H-F] or low frequency [L-F]). H-F is set at 100 Hz and L-F is set at 4 Hz. A baseline assessment is taken with the visual analog score (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oxford Knee Score, and Lequesne index. They were instructed to self-administer the TENS therapy as per protocol and followed up at the 4th and 12th week to be reevaluated on the above scores. Results:The final results show that both H-F and L-F groups showed improvement in all parameters of the VAS, WOMAC index, Oxford Knee Score, and Lequesne index (73%). Only the pain component of Lequesne index, activities of daily living component of Lequesne index, total Lequesne index, and pain component of WOMAC index shows a statistically significant difference, favoring the H-F group. The H-F group yields a faster result; however, with time the overall effect remains the same in both groups. Conclusion:Both H-F and L-F groups show improvement in all the component of Lequesne index, Oxford Knee Score, WOMAC index, and VAS with no statistical difference between the two groups. Although H-F yields a faster result, not everyone is able to tolerate the intensity. Therefore, the selection of H-F or L-F should be done on case basis depending on the severity of symptoms, patient's expectation, and patient's ability to withstand the treatment therapy. Based on this 12th week follow-up, both groups will continue to improve with time. A longer study should be conducted to see it this improvement will eventually plateau off or continue to improve until the patient is symptom free. 10.13107/jocr.2020.v10.i03.1772
Efficacy and safety of transcutaneous electrical nerve stimulation (TENS) for acute and chronic pain in adults: a systematic review and meta-analysis of 381 studies (the meta-TENS study). BMJ open OBJECTIVE:To investigate the efficacy and safety of transcutaneous electrical nerve stimulation (TENS) for relief of pain in adults. DESIGN:Systematic review and meta-analysis. DATA SOURCES:Medline, Cochrane Central, Embase (and others) from inception to July 2019 and updated on 17 May 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION:Randomised controlled trials (RCTs) comparing strong non-painful TENS at or close to the site of pain versus placebo or other treatments in adults with pain, irrespective of diagnosis. DATA EXTRACTION AND SYNTHESIS:Reviewers independently screened, extracted data and assessed risk of bias (RoB, Cochrane tool) and certainty of evidence (Grading and Recommendations, Assessment, Development and Evaluation). Mean pain intensity and proportions of participants achieving reductions of pain intensity (≥30% or 50%) during or immediately after TENS. Random effect models were used to calculate standardised mean differences (SMD) and risk ratios. Subgroup analyses were related to trial methodology and characteristics of pain. RESULTS:The review included 381 RCTs (24 532 participants). Pain intensity was lower during or immediately after TENS compared with placebo (91 RCTs, 92 samples, n=4841, SMD=-0·96 (95% CI -1·14 to -0·78), moderate-certainty evidence). Methodological (eg, RoB, sample size) and pain characteristics (eg, acute vs chronic, diagnosis) did not modify the effect. Pain intensity was lower during or immediately after TENS compared with pharmacological and non-pharmacological treatments used as part of standard of care (61 RCTs, 61 samples, n=3155, SMD = -0·72 (95% CI -0·95 to -0·50], low-certainty evidence). Levels of evidence were downgraded because of small-sized trials contributing to imprecision in magnitude estimates. Data were limited for other outcomes including adverse events which were poorly reported, generally mild and not different to comparators. CONCLUSION:There was moderate-certainty evidence that pain intensity is lower during or immediately after TENS compared with placebo and without serious adverse events. PROSPERO REGISTRATION NUMBER:CRD42019125054. 10.1136/bmjopen-2021-051073
Electroacupuncture activated local sympathetic noradrenergic signaling to relieve synovitis and referred pain behaviors in knee osteoarthritis rats. Frontiers in molecular neuroscience Introduction:Recent research has focused on the local control of articular inflammation through neuronal stimulation to avoid the systemic side effects of conventional pharmacological therapies. Electroacupuncture (EA) has been proven to be useful for inflammation suppressing and pain reduction in knee osteoarthritis (KOA) patients, yet its mechanism remains unclear. Methods:In the present study, the KOA model was established using the intra-articular injection of sodium monoiodoacetate (MIA) (1 mg/50 μL) into the knee cavity. EA was delivered at the ipsilateral ST36-GB34 acupoints. Hind paw weight-bearing and withdrawl thresholds were measured. On day 9, the histology, dep enrichment proteins, cytokines contents, immune cell population of the synovial membrane of the affected limbs were measured using HE staining, Masson staining, DIA quantitative proteomic analysis, flow cytometry, immunofluorescence staining, ELISA, and Western Blot. The ultrastructure of the saphenous nerve of the affected limb was observed using transmission electron microscopy on the 14th day after modeling. Results:The result demonstrated that EA intervention during the midterm phase of the articular inflammation alleviated inflammatory pain behaviors and cartilage damage, but not during the early phase. Mid-term EA suppressed the levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 in the synovium on day 9 after MIA by elevating the level of sympathetic neurotransmitters Norepinephrine (NE) in the synovium but not systemic NE or systemic adrenaline. Selective blocking of the sympathetic function (6-OHDA) and β2-adrenergic receptor (ICI 118,551) prevented the anti-inflammatory effects of EA. EA-induced increment of the NE in the synovium inhibited the CXCL1-CXCR2 dependent overexpression of IL-6 in the synovial macrophages in a β2-adrenergic receptor (AR)-mediated manner. Discussion:These results revealed that EA activated sympathetic noradrenergic signaling to control local inflammation in KOA rats and contributed to the development of novel therapeutic neurostimulation strategies for inflammatory diseases. 10.3389/fnmol.2023.1069965
[Anti-inflammatory and synovial-opioid system effects of electroacupuncture intervention on chronic pain in arthritic rats]. Jiang Yongliang,He Xiaofen,Yin Xiaohu,Shen Yafang,Fang Jianqiao Zhongguo zhen jiu = Chinese acupuncture & moxibustion OBJECTIVE:To observe the analgesic effect of electroacupuncture (EA) on collagen-induced arthritis (CIA) rats and its regulating effect on inflammation reaction and the endogenous opioid system of synovial tissues. Methods A total of 30 healthy male Wistar rats were randomly divided into a control group, a model group and an EA group, 10 rats in each one. The chronic pain model of CIA rats was made by cattle type-II collagen in the model group and EA group. Rats in the EA group were treated with EA at "Zusanli" (ST 36) and "Kunlun" (BL 60) for 30 min from 16th day after model establishment, once a day for consecutive 10 days. Rats in the control group did not receive any treatment. Rats in the model group were treated with fixation as the EA group. Threshold of pain, arthritis index, paw swelling were measured before model establishment and 16 d, 20 d, 23 d and 25 d after model establishment. The levels of beta-endorphin (β-END), met-enkephalin (met-ENK), dynorphin A (Dyn A) were measured by radioimmunoassay; the mRNA expressions of mu opioid receptor (MOR), kappa opioid receptor (KOR) and delta opioid receptor (DOR) in synovial tissues of CIA rats were detected by I quantitative polymerase chain reaction (qPCR). RESULTS:Compared with the control group, threshold of pain was reduced (all P<0. 01), arthritis index was increased (all P<0. 01) and paw swelling was increased (all P<0. 01) in the model group on the 16th day, 20th day, 23rd day, 25th day after model establishment. Compared with the model group, the threshold of pain was increased in the EA group (all P<0. 01), arthritis index and paw swelling were reduced (all P<0. 01) on the 23rd day and 25th day after model establishment. Compared with the control group, the level of Dyn A in synovial tissues of CIA rats was increased in the model group (P<0. 01); the mRNA expressions of MOR, KOR and DOR were down-regulated lower than 0. 5 fold of normal level. Compared with the model group, the level of β-END in synovial tissues of the knee joint was increased in the EA group (P<0. 05), and the mRNA expressions of MOR, KOR and DOR in synovial tissues of CIA rats were up-regulated more than 2 folds of normal level. CONCLUSION:The intervention of EA on chronic pain of CIA rats is superior, which is likely to be related with effects of EA on anti-inflammation and up-regulation of synovial tissue β-END and MOR, KOR, DOR.
Inhibition of GSK-3β Alleviates Collagen II-Induced Rheumatoid Arthritis in Rats. Zhou Haiyan,Liu Jun,Zeng Jiashun,Hu Bailong,Fang Xiuyi,Li Long Medical science monitor : international medical journal of experimental and clinical research BACKGROUND:Glycogen synthase kinase-3β (GSK-3β) inhibitor is a serine/threonine kinase with an inhibitory role in glycogen synthesis, which is essential in inflammatory and immunological diseases. The purpose of our study was to determine if TDZD-8 can alleviate collagen II-induced rheumatoid arthritis in rats. MATERIAL/METHODS:Twenty collagen II-induced rheumatoid arthritis rats were treated with selective GSK-3β inhibitor. The effects of GSK-3β inhibition on collagen II-induced rheumatoid arthritis in the rats were evaluated by paw edema, histological examination of arthritic synovium, radiographic examination of knee joint, and the level of inflammation mediators such as prostaglandin E2, 5-hydroxytryptamin, and histamine. The level of cytokines such as IL-6, IL-12, IL-10, and TNF-α, was examined by Elisa. RESULTS:GSK-3β inhibitor significantly reduced the development of rheumatoid arthritis in rats. The levels of inflammation mediators such as prostaglandin E2, 5-hydroxytryptamin, and histamine were decreased in the TDZD-8 group. Serum levels of IL-6, IL-12, and TNF-α were significantly reduced in the TDZD-8 group compared with the RA group. CONCLUSIONS:Treatment with GSK-3β inhibitor suppressed inflammatory response in RA rats. These findings suggest that the inhibition of GSK-3β can be an effective treatment for RA. 10.12659/msm.897739
Changes in preprotachykinin mRNA expression and substance P levels in dorsal root ganglia of monoarthritic rats: comparison with changes in synovial substance P levels. Garrett N E,Kidd B L,Cruwys S C,Tomlinson D R Brain research We have measured changes in the expression of gamma-preprotachykinin mRNA and levels of the neuropeptide substance P in the lumbar 4 and 5 dorsal root ganglia at various time points following the induction of an antigenic monoarthritis in the rat knee. The results were compared with changes in substances P levels in the knee joint synovium during acute and chronic phases of the disease. On day 3 post-induction, there was a significant increase in the expression of gamma-preprotachykinin mRNA in the dorsal root ganglia. Concomitant with this increase in message was a rise in the levels of substance P in the dorsal root ganglia. On days 7, 10 and 21, mRNA expression had returned to control values whereas ganglion peptide levels were significantly below controls. In contrast there was little change in the total substance P levels in the synovium on days 1 and 3 despite the observed changes in the ganglia. By day 10, however, synovial levels had risen significantly above control values and remained elevated thereafter. Our results show a transitory increase in substance P synthesis after induction of an antigenic monoarthritis. This response is not mirrored in the periphery where there is no initial change in total substance P levels perhaps reflecting increased degradation be enzymes known to be present within inflamed tissue. Paradoxically synovial substance P levels are increased in the latter phases of the model which may serve to modify the inflammatory response. 10.1016/0006-8993(95)00066-y
Analgesic Tolerance Development during Repetitive Electric Stimulations Is Associated with Changes in the Expression of Activated Microglia in Rats with Osteoarthritis. Hahm Suk-Chan,Lee Jin Seung,Yoon Young Wook,Kim Junesun Biomedicines Electric stimulation is used for managing osteoarthritic (OA) pain; however, little is known about the development of analgesic tolerance during repeated stimulations and the relation of spinal microglia with OA pain. We investigated the changes in the analgesic effects of repeated electric stimulations and the relation between the development of analgesic tolerance and spinal microglial expression in rats with OA. To induce OA, monosodium iodoacetate was injected into the synovial space of the right knee joint of the rats ( = 185). Repeated high frequency, low frequency, or sham transcutaneous electric nerve stimulation (TENS) was performed to the ipsilateral knee joint for 20 min in rats with OA ( = 45). Minocycline or minocycline plus TENS (HF, LF, or sham) was treated in OA rats with repeated TENS-induced tolerance ( = 135). Immunohistochemistry of the microglia in the L3-L5 spinal segments was performed. Knee joint pain during passive movement of the knee joint were quantified using the knee-bend score and the proportion of activated microglia was calculated as primary variables. Paw withdrawal threshold (hypersensitivity to mechanical stimuli) was assessed and the resting and activated microglia were counted as secondary variables. Repeated applications decreased the analgesic effect of TENS on OA pain and failed to reduce the expression of activated microglia in the spinal cord. However, spinal microglial inhibition by minocycline restored the analgesic effect of TENS on OA pain in TENS-tolerant OA rats. TENS combined with minocycline treatment improved knee joint pain and mechanical hypersensitivity in TENS-tolerant OA rats, and inhibited the expression of activated microglia in the spinal cord. These results suggest a possible relationship between repetitive electric stimulation-induced analgesic tolerance for OA pain control and changes in microglia activation. 10.3390/biomedicines8120575
Ganghwaljetongyeum, an anti-arthritic remedy, attenuates synoviocyte proliferation and reduces the production of proinflammatory mediators in macrophages: the therapeutic effect of GHJTY on rheumatoid arthritis. Jeoung Bo-Ram,Lee Kyung Dong,Na Chang-Su,Kim Young-Eok,Kim BoA,Kim Young Ran BMC complementary and alternative medicine BACKGROUND:Ganghwaljetongyeum (GHJTY), a complex herbal decoction, is used to treat rheumatoid arthritis. However, the action mechanism of GHJTY is not still unclear on rheumatoid arthritis. In this study, we examined the beneficial effects and the action mechanisms of GHJTY on synoviocyte proliferation and inflammatory mediators. METHODS:To test the effect of GHJTY on synoviocyte proliferation, HIG-82 cells, rabbit knee synovial membrane cells, were treated with GHJTY under IL-1β. To evaluate the effects of GHJTY on proinflammatory mediators, we tested cytokine levels in RAW264.7 cells. RESULTS:Proliferation of HIG-82 cells was significantly inhibited by GHJTY treatment. We found that GHJTY caused cytoskeleton damage to HIG-82 cells. In contrast, treatment of GHJTY did not show any cytotoxicity to other different origin cell lines, HeLa and RAW264.7 cells. GHJTY inhibited IL-1β-mediated NF-κB activation in HIG-82 cells and reduced the LPS-mediated production of proinflammatory cytokines, TNF-α, IL-12, and NO in RAW264.7 cells. In addition, the expression of cyclooxygenase in LPS-activated RAW264.7 cells was also decreased by GHJTY treatment. CONCLUSIONS:These results suggest that GHJTY might effectively attenuate rheumatoid arthritis by inhibiting the production of proinflammatory mediators and the proliferation of synoviocytes. 10.1186/1472-6882-13-47
Endocannabinoids inhibit neurogenic inflammation in murine joints by a non-canonical cannabinoid receptor mechanism. Krustev Eugene,Muley Milind M,McDougall Jason J Neuropeptides Neurogenic inflammation is a local inflammatory response that is driven by the peripheral release of neuropeptides from small diameter afferents which occurs in many organs including joints. The knee joint has a rich endocannabinoid system which has been shown to decrease acute synovitis. The aim of this study was to investigate the influence of joint afferents on leukocyte-endothelial interactions within the synovial microcirculation of mice and determine the role of endocannabinoids on this inflammatory response. Electrical, antidromic stimulation of the saphenous nerve decreased leukocyte rolling at the lowest frequency tested (0.5Hz), while increasing leukocyte rolling at higher frequencies (2.0 and 5.0Hz). The leukocyte rolling effect of nerve stimulation was completely abolished by pre-treating the knee with the vasoactive intestinal peptide antagonist VIP; however, neither calcitonin gene related peptide nor substance P antagonism had an effect on this neurogenic inflammatory response. Treating knees with the endocannabinoid breakdown inhibitor URB597 completely blocked leukocyte rolling and this effect could be reversed with the non-canonical cannabinoid antagonist O-1918. These results provide evidence that antidromic stimulation of the mouse saphenous nerve promotes leukocyte rolling within the synovial microcirculation, and that endocannabinoids can attenuate this neurogenic inflammatory response. 10.1016/j.npep.2016.08.007
Focused Ultrasound (FUS) for Chronic Pain Management: Approved and Potential Applications. Neurology research international Chronic pain is one of the leading causes of disability and disease burden worldwide, accounting for a prevalence between 6.9% and 10% in the general population. Pharmacotherapy alone results ineffective in about 70-60% of patients in terms of a satisfactory degree of pain relief. Focused ultrasound is a promising tool for chronic pain management, being approved for thalamotomy in chronic neuropathic pain and for bone metastases-related pain treatment. FUS is a noninvasive technique for neuromodulation and for tissue ablation that can be applied to several tissues. Transcranial FUS (tFUS) can lead to opposite biological effects, depending on stimulation parameters: from reversible neural activity facilitation or suppression (low-intensity, low-frequency ultrasound, LILFUS) to irreversible tissue ablation (high-intensity focused ultrasounds, HIFU). HIFU is approved for thalamotomy in neuropathic pain at the central nervous system level and for the treatment of facet joint osteoarthritis at the peripheral level. Potential applications include HIFU at the spinal cord level for selected cases of refractory chronic neuropathic pain, knee osteoarthritis, sacroiliac joint disease, intervertebral disc nucleolysis, phantom limb, and ablation of peripheral nerves. FUS at nonablative dosage, LILFUS, has potential reversible and tissue-selective effects. FUS applications at nonablative doses currently are at a research stage. The main potential applications include targeted drug and gene delivery through the Blood-Brain Barrier, assessment of pain thresholds and study of pain, and reversible peripheral nerve conduction block. The aim of the present review is to describe the approved and potential applications of the focused ultrasound technology in the field of chronic pain management. 10.1155/2021/8438498
Extensile Anterior and Posterior Knee Exposure for Complete Synovectomy of Diffuse Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis). JBJS essential surgical techniques Diffuse tenosynovial giant cell tumor (TGCT), also known as pigmented villonodular synovitis, is a benign, neoplastic disease of the synovium that can lead to joint destruction, osteoarthritis, and long-term morbidity. Often, there is extra-articular involvement in the intercondylar notch and posterior soft tissues. A complete anterior and posterior synovectomy of the knee is indicated for treating diffuse TGCT when the anterior and posterior compartments of the knee joint are involved. Additionally, either an anterior or posterior synovectomy may be performed when the TGCT is limited to 1 compartment of the knee. Although an anterior synovectomy is relatively straightforward technically, a posterior synovectomy is challenging because of the presence of the neurovascular and muscular structures, which limit access, and because of the infrequency of the procedure. Description:The surgical technique for open anterior and posterior knee synovectomy is performed under 1 anesthetic via separate exposures with the patient initially supine and then prone. In cases of focal TGCT, in which both the anterior and posterior compartments are involved, either an anterior or posterior approach can be utilized in isolation to target the affected compartment. The anterior approach is performed via anteromedial parapatellar arthrotomy, with care to preserve the meniscal attachments and ligaments. Once the suprapatellar pouch is visualized, all tissue deep to the quadriceps muscle and tendon, extending around to the femoral periosteum, is excised en bloc. Attention is then turned to the undersurface of the patella, fat pad, distal aspect of the femur, and proximal aspect of the tibia. The tumor may be embedded within the fat pad and must be removed. Any tumor remnants within the medial or lateral gutter or beneath the menisci are excised with use of a standard or pituitary rongeur or curets. The quadriceps tendon, subcutaneous tissue, and skin are closed over a deep drain, and the patient is turned prone and re-prepared for the posterior approach. The posterior synovectomy utilizes an S-shaped incision either superolateral to inferomedial or superomedial to inferolateral, depending on the location of the TGCT. The popliteal artery and vein and the tibial and common peroneal nerves are identified, mobilized, and protected during retraction. This step requires ligating the geniculate and other small branches of the popliteal artery and vein. To expose the posterior femoral condyle, the medial and/or lateral heads of the gastrocnemius must be tagged and released by dividing the myotendinous origin from the posterior aspect of the femur at the proximal extent of the condyle. Alternatives:Although surgical resection is the primary treatment for TGCT, nonsurgical alternatives include radiation therapy (either external beam or radiosynoviorthesis) and the use of pharmacologic agents. Radiation therapy is associated with complications such as irreversible skin changes, arthrofibrosis, arthritis, osteonecrosis, and radiation-induced sarcoma. Systemic agents such as tyrosine kinase inhibitors (e.g., nilotinib and imatinib) or agents targeting the CSF-1 (colony-stimulating factor-1) pathway (e.g., pexidartinib and emactuzumab) are active against TGCT. The agents are typically employed in recurrent, advanced, and unresectable situations in which surgical morbidity would outweigh the therapeutic benefit. Aside from open synovectomy, arthroscopic synovectomy-usually anterior-has been utilized by some centers. Rationale:To our knowledge, there is no Level-I study indicating the superiority of 1 surgical technique over the other treatments for diffuse TGCT. Anterior arthroscopic synovectomy, in isolation, for diffuse TGCT has demonstrated recurrence rates as high as 92% to 94%. Recent studies comparing anterior and posterior open and arthroscopic synovectomy have demonstrated mixed results, are limited by being retrospective, and are subject to selection bias because of the open synovectomy being selected for more extensive disease. The mixed results may a result of variation in both tumor size and location about the knee joint. The benefit of an open anterior and posterior synovectomy is that it can provide optimal exposure for large and extra-articular tumor masses that would not be accessible using an arthroscopic approach and allows for complete, gross total excision without morsellization of the tumor. The surgeon must be familiar and facile with vascular dissection techniques, even if the soft tissues surrounding the vascular structures are preserved as much as possible, in an effort to minimize postoperative edema. Expected Outcomes:Open anterior and posterior synovectomy provides improved exposure for large and extra-articular tumor masses and has a 5-year recurrence-free survival of 29% to 33%. Pain associated with diffuse TGCT has been demonstrated to improve in 59% of cases, with swelling reported to improve by 72% in patients following surgical intervention. No significant difference has been reported when comparing open versus arthroscopic synovectomy in terms of arthritic progression, with 8% of patients progressing to a total knee arthroplasty at a mean follow-up of 40 months. Important Tips:Careful preoperative planning is crucial: note all locations of posteriorly located tumor on magnetic resonance imaging and in relation to anatomic landmarks and neurovascular structures in order to guide dissection.It can be advantageous to have multiple blunt retractor options available when dissecting in tight spaces.Be prepared for vessel ligation with free ties, vessel clips, and additional clamps.The technical ability to dissect and mobilize the popliteal vessels is essential, but this step can be tedious.At the time of incision, preserve the integrity of the popliteal fascia to facilitate a good closure later, as this step avoids the herniation of tissues in the popliteal fossa. Because this fascial tissue is fragile, the use of a monofilament rather than braided suture in addition to the placement of far-near-near-far-type figure-of-8 sutures minimizes the risk of tearing the fascia during reapproximation.To ease retraction of the soft tissues, slightly flex the knee to relax the hamstring and other muscles and neurovascular structures. This will also reduce the risk of a postoperative nerve palsy.Although separate instruments for the anterior and posterior portions of the procedure are not necessary, separate drapes, gown, and gloves and other preoperative preparation should be readied in advance for the second portion of the procedure in order to save operative time. Acronyms & Abbreviations:PVNS = pigmented villonodular synovitisROM = range of motionMRI = magnetic resonance imagingGastroc = gastrocnemiusPDS = polydioxanone sutureCAM = controlled ankle motionASA = acetylsalicylic acid (aspirin). 10.2106/JBJS.ST.21.00035
Requirement of metabotropic glutamate receptors for the generation of inflammation-evoked hyperexcitability in rat spinal cord neurons. Neugebauer V,Lücke T,Schaible H G The European journal of neuroscience In the central nervous system the transmitter L-glutamate activates both ionotropic receptors coupled to cation channels and metabotropic receptors coupled to G-proteins. The role of metabotropic receptors in the processing of mechanosensory and nociceptive information was studied in a subset of spinal cord neurons with afferent input from the knee joint in anaesthetized rats using electrophysiological methods. The ionophoretic administration of L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist at the metabotropic receptor, had no effect on the responses to innocuous and noxious pressure applied to the normal knee joint, although the antagonist prevented the potentiation of these responses evoked by the ionophoretic administration of a specific agonist at the metabotropic receptor, trans-(+/-)-1-amino-(1S,3R)-cyclopentane-dicarboxylic acid (t-ACPD). By contrast, in neurons that were rendered hyperexcitable by acute inflammation in the knee joint L-AP3 reduced the responses to pressure applied to the knee. When L-Ap3 was applied during induction of inflammation and throughout the subsequent 1.5 h the spinal neurons did not develop hyperexcitability over this time period. L-AP3 did not impair the activation of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors by the specific agonists. We conclude that spinal metabotropic glutamate receptors are not involved in the mediation of responses to innocuous and noxious mechanical stimuli applied under normal conditions. They are required, however, for the generation of inflammation-evoked hyperexcitability of spinal cord neurons, a form of functional plasticity underlying the painfulness in pathophysiological conditions such as inflammation.
Anti-inflammatory effects of the extract of Gnaphalium affine D. Don in vivo and in vitro. Huang Doudou,Chen Yanhong,Chen Wansheng,Liu Ying,Yao Fengyan,Xue Dan,Sun Lianna Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Gnaphalium affine D. Don (GA) has been traditionally used as a medicinal herb in China for the treatment of many ailments including rheumatoid arthritis. However, the anti-arthritic mechanism of GA has still not been demonstrated. This study aims to reveal the anti-inflammatory activity and anti-arthritic mechanism of ethanol extract of G. affine D. Don. MATERIALS AND METHODS:Anti-inflammatory potential of GA was analyzed in vivo in carrageenan induced mice paw edema (acute study). Also, in vivo study was applied in collagen-induced arthritis (CIA) rats. In vitro experiments for analyzing the anti-inflammatory potential of GA were performed on rat alveolar macrophages cell line (NR8383). Analysis of nitric oxide release in NR8383 cells was done by Griess reaction. RT-PCR and western blotting experiment was performed to analyze the expression of phosphorylated p65 and IκBα/β-actin in NF-κB pathway. The production of TNF-α, IL-1β, and COX-2 in NR8383 cells were measured by enzyme-linked immunosorbent assay. The chemical profile of GA was analyzed by HPLC-VWD. RESULTS:GA significantly reduced the paw volume in carrageenan induced rat paw edema rat at different doses (300 and 600 mg/kg), compared with the standard indomethacin treatment. In CIA, GA can obviously ameliorate the inflammatory symptom, including cytokine, histological symptom and paw swelling. In the vitro study, GA was able to reduce the nitric oxide (NO) levels in NR8383 cells that had been stimulated with lipopolysaccharide (LPS). The level of TNF-α, IL-1β, and COX-2 was also decreased with GA treatment in NR8383 cells that had been stimulated with lipopolysaccharide (LPS). Interestingly, GA was found to decrease the level of phosphorylated p65 and IκBα in NR8383 cells. Fifteen compounds were identified by HPLC-VWD with the reference substances and verified by LC-MS. CONCLUSIONS:The results of the experiment scientifically validated its traditional use in inflammatory conditions. 10.1016/j.jep.2015.11.010
Release of immunoreactive substance P in the spinal cord during development of acute arthritis in the knee joint of the cat: a study with antibody microprobes. Schaible H G,Jarrott B,Hope P J,Duggan A W Brain research In anaesthetized spinal cats, the release of immunoreactive substance P in the spinal cord during development of an acute inflammation in one knee joint was studied with antibody microprobes. The microprobes bore antibodies directed to the C- or N-terminus of substance P. With the normal knee joint, innocuous mechanical stimuli (flexion, pressure) did not result in spinal release of immunoreactive substance P. Following injection of kaolin and carrageenan into a knee, evidence for release of substance P following joint stimulation was found in 7 of 10 cats. Such release did not occur for several hours after joint injection and was detected predominantly in the superficial dorsal horn, the dorsal columns and at the dorsal surface of the spinal cord. In some experiments release was detected in the deep dorsal horn and upper ventral horn. Release of immunoreactive substance P required periods of mechanical stimulation such as flexion of, or pressure to, the inflamed joint. The failure to detect central release of substance P from stimulation of normal joints, and the release of substance P, after a delay, from inflamed joints, suggest that the fibres releasing this compound require sensitization by inflammatory mediators before they are excited by joint stimuli. 10.1016/0006-8993(90)90830-5
Hydrogen sulfide releasing naproxen offers better anti-inflammatory and chondroprotective effect relative to naproxen in a rat model of zymosan induced arthritis. Dief A E,Mostafa D K,Sharara G M,Zeitoun T H European review for medical and pharmacological sciences OBJECTIVE:Hydrogen sulfide (H2S) is rapidly gaining ground as a physiological mediator of inflammation, but there is no clear consensus as to its precise role in inflammation. Therefore, this study was undertaken to evaluate the effects of ATB-346 as a novel H2S-releasing naproxen compared to naproxen, as a traditional non-steroidal anti-inflammatory drug on zymosan induced mono-arthritis in rats. MATERIALS AND METHODS:Male Wistar rats (n=48) were randomly assigned to four main groups: normal control, untreated arthritis, Naproxen and ATB-346 treated groups. Mono-arthritis was induced by intra-articular injection of zymosan into the knee joints. Mechanical hypernociception and joint swelling were evaluated at 6 hours and 5 days. Inflammatory cellular recruitment and adherence, tumor necrosis factor alpha, nuclear factor kappa β, total sulfide levels, and histological changes were evaluated in knee lavages, blood or joint tissues at selected time points. RESULTS:Zymosan injection evoked knee inflammation and pain as characterized by mechanical hypernociception, impaired gait, joint swelling with inflammatory exudation and histological changes. Treatment with ATB-346 attenuated nociceptive responses, inflammatory cellular and biochemical changes in comparison to naproxen. Only ATB-346 was able to suppress neutrophil adherence and to preserve normal articular structure. CONCLUSIONS:H2S releasing naproxen represents an advancement over the parent drug, naproxen. Apart from the superior anti-inflammatory and anti-noceiceptive activity, ATB-346 offered a distinguished chondroprotective effect and is almost devoid from naproxen deleterious effects on articular cartilage.
N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint. Neugebauer V,Lücke T,Schaible H G Journal of neurophysiology 1. In 22 anesthetized rats we studied the involvement of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the generation and maintenance of hyperexcitability in spinal cord neurons with knee input that develops in the course of an acute inflammation in the knee. In all experiments one neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the intra-articular injections of kaolin and carrageenan into the joint cavity. In most experiments multibarrel electrodes were used to administer specific NMDA and non-NMDA antagonists ionophoretically close to the neuron to test their effects on the inflammation-evoked changes. 2. Six neurons in the deep dorsal horn in six rats were used to establish the time course of the development of hyperexcitability in the untreated animal. In control periods of up to 3 h, the responses to mechanical stimuli and the receptive fields were stable. After induction of inflammation, the neurons developed increased responsiveness to mechanical stimuli applied to the injected knee but also to mechanical stimuli applied to the ipsilateral ankle and paw (including a reduction in the mechanical threshold in nociceptive specific neurons). The receptive fields expanded in five out of six neurons. The changes of responsiveness occurred mainly in the 2nd to 3rd h after the injection of kaolin. 3. In four rats three to four intravenous injections of the NMDA antagonist ketamine (2 mg/kg) were given during the injections of kaolin and carrageenan and in the following periods (up to 101 min postkaolin). During this treatment none of the four neurons exhibited the changes of responsiveness that were usually seen in control animals, although swelling of the knee developed in the same fashion as in control rats. Similarly, the generation of hyperexcitability was prevented when the NMDA antagonists ketamine and DL-2-amino-5-phosphonovalerate (AP5) were administered ionophoretically (ketamine in 4, AP5 in 2 rats) during the injections of kaolin and carrageenan and up to 100 min postkaolin. The doses of ketamine and AP5 were sufficient to reduce the responses to NMDA, whereas the responses to the non-NMDA agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were not influenced. 4. The ionophoretic application of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) during the injections of the kaolin and carrageenan and up to 103 min postkaolin also prevented the generation of hyperexcitability in six neurons in six rats.(ABSTRACT TRUNCATED AT 400 WORDS) 10.1152/jn.1993.70.4.1365
Anti-inflammatory effects of botulinum toxin type a in a complete Freund's adjuvant-induced arthritic knee joint of hind leg on rat model. Yoo Ki Yeon,Lee Hee Su,Cho Young Kyung,Lim You Sun,Kim Yi Seul,Koo Jung Hoi,Yoon Se Jin,Lee Jung Hwan,Jang Ki Hyo,Song Sun Hong Neurotoxicity research The objective of the study is to verify histopathologically the anti-inflammatory effect of botulinum toxin type A (BoNT-A) in a Complete Freund's Adjuvant (CFA)-induced arthritic knee joint of hind leg on rat model using immunofluorescent staining of anti-ionized calcium-binding adaptor molecule 1 (Iba-1) and interleukin-1β (IL-1β) antibody. Twenty-eight experimental rats were injected with 0.1 ml of CFA solution in the knee joint of the hind leg bilaterally. Three weeks after CFA injection, the BoNT-A group (N = 14) was injected with 20 IU (0.1 ml) of BoNT-A bilaterally while the saline group (N = 14) was injected with 0.1 ml of saline in the knee joint of the hind leg bilaterally. One and two weeks after BoNT-A or saline injection, joint inflammation was investigated in seven rats from each group using histopathological and immune-fluorescent staining of Iba-1 and IL-1β antibody. The number of Iba-1 and IL-1β immune-reactive (IR) cells was counted in the BoNT-A and saline groups for comparison. There was a significant reduction in joint inflammation and destruction in the BoNT-A group at 1 and 2 weeks after BoNT-A injection compared with the saline group. The binding of Iba-1 and IL-1β antibody was significantly lower in the BoNT-A group than the saline group at 1 and 2 weeks after BoNT-A injection. The number of Iba-1 and IL-1β-IR cells at 1 and 2 weeks after the injection of BoNT-A were significantly different from the corresponding number of Iba-1 and IL-1β-IR cells in the saline group. To conclude, BoNT-A had an anti-inflammatory effect in a CFA-induced arthritic rat model, indicating that BoNT-A could potentially be used to treat inflammatory joint pain. 10.1007/s12640-013-9447-7
The role of neutrophils in acute and chronic inflammation in rats. Ezeamuzie I C,Njoku A C African journal of medicine and medical sciences The effect of neutropenia on acute and chronic inflammatory oedema in rats was assessed using histamine, carrageenan and Freund's complete adjuvant as inducers. Neutropenia (about 85% reduction in peripheral blood neutrophil count) was induced with intraperitoneal administration of 2.5 mg/kg methotrexate for three consecutive days. Acute paw oedemas induced with carrageenan and Freund's complete adjuvant, but not that induced by histamine, were significantly decreased in neutropenic animals compared with controls. In adjuvant-induced chronic knee swelling (Adjuvant arthritis), neutropenia produced small, statistically non-significant, suppressive effect. In contrast, it significantly suppressed adjuvant-induced chronic paw swelling, although suppression was observed only in the late phase component of the swelling. The results suggest that neutrophils are involved in certain acute and chronic inflammatory responses but not in others.
Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Boettger Michael K,Hensellek Susanne,Richter Frank,Gajda Mieczyslaw,Stöckigt Renate,von Banchet Gisela Segond,Bräuer Rolf,Schaible Hans-Georg Arthritis and rheumatism OBJECTIVE:The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy. METHODS:Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation). RESULTS:In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint. CONCLUSION:Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief. 10.1002/art.23608
Therapeutic effect of dimethyl dimethoxy biphenyl dicarboxylate on collagen-induced arthritis in rats. Talaat Roba M,Abo-El-Atta Amira S,Farou Sabah M,El-Dosoky Karima I Chinese journal of integrative medicine OBJECTIVE:To study the effect of oral administration of dimethyl dimethoxy biphenyl dicarboxylate (DDB) on adjusting angiogeneic/inflammatory mediators and ameliorating the pathology of bones in rats with collagen-induced arthritis (CIA). METHODS:Wistar rat model of CIA was set up using bovine collagen type II. Fifty rats were divided into five groups randomly: normal, CIA model, DDB treatment, methotrexate (MTX) treatment, and combined DDB+MTX treatment. Ankle joints of rats were imaged with digital X-ray machine to show the destruction of joints. Fore and hind paw and knee joints were removed above the ankle joint then processed for haematoxylin and eosin staining. Plasma levels of vascular endothelial growth factor (VEGF), platelet derived growth factor, interleukin-8 (IL-8), IL-4, tumor necrosis factor α (TNF-α), and cyclooxygenase-2 (COX-2) were quantified by enzyme-linked immunosorbent assay. Nitric oxide levels were detected by Griess reagent. RESULTS:Compared with the CIA model group, a remarkable reduction in various angiogenic (VEGF and IL-8) and inflammatory mediators (TNF-α, IL-4 and COX-2) after treatment with DDB either alone or combined with MTX P<0.05 or P<0.01). Histopathological and X-ray findings were confirmatory to the observed DDB anti-arthritic effect. The DDB-treated group showed amelioration in signs of arthritis which appeared essentially similar to normal. CONCLUSION:Our data shed light on the therapeutic efficacy of DDB in experimental rheumatoid arthritis (RA) compared with a choice drug (MTX) and it may be offered as a second-line drug in the treatment of RA. 10.1007/s11655-014-1746-1
RvD1 disrupts nociceptor neuron and macrophage activation and neuroimmune communication, reducing pain and inflammation in gouty arthritis in mice. British journal of pharmacology BACKGROUND AND PURPOSE:Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature. EXPERIMENTAL APPROACH:Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1β production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy. KEY RESULTS:RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1β production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1β production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages. CONCLUSIONS AND IMPLICATIONS:This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1. 10.1111/bph.15897
Long term effects of intra-articular botulinum toxin A for refractory joint pain. Mahowald M L,Singh J A,Dykstra D Neurotoxicity research UNLABELLED:The purpose of this case series review is to describe our 12 month clinical experience with intra-articular injections of Botulinum toxin Type A (BoNT/A) for refractory joint pain. Eleven patients with chronic arthritis who had failed treatment with oral and/or intra-articular medications and were not surgical candidates were referred to us for management of moderate to severe refractory joint pain in 15 joints. The use of BoNT/A to treat joint pain is a non-FDA approved "off label" treatment with potential side effects. After a detailed explanation of the joint injection procedure, signed informed consent was obtained for the procedure. Fifteen joints were injected with BoNT/A (Allergan, Inc): six lower extremity joints (3 knees, 3 ankles) with 25-50 units and nine shoulders with 50-100 units. Patients were followed for one year or longer. Maximum relief of pain was measured by comparing baseline pain on a numeric rating scale (0-10) to pain at the time of maximum relief (paired t-test). Maximum improvement in function was assessed using paired t-tests for improvement in active flexion and abduction for the shoulder joint, and by the time to perform sit to stand ten times (the timed stands test, TST) for the lower extremity joints. RESULTS:Two patients were female and nine were male, aged 42-82 years. Five had osteoarthritis (OA), five had rheumatoid arthritis (RA) and one had psoriatic arthritis. All patients were on analgesic and/or anti-inflammatory medications and all joints had previous intra-articular steroid or viscosupplement injections with inadequate or unsatisfactory benefit. A clinically and statistically significant improvement was noted after IA-BoNT/A injections. The mean maximum decrease in lower extremity joint pain was 55% (p =0.02) and the 36% (p =0.044) improvement in the Timed Stands Test was noted at four to ten weeks after injection. There was a 71% mean maximum reduction in shoulder pain severity from 8.2 +/- 1.1 to 2.4 +/- 1.9 (p <0.001). Active range of motion increased 67% in flexion (from 67.8 +/- 27.6 to 113.3 +/- 46.6 degrees, p =0.001) and 42% in abduction (from 50 +/- 18.5 degrees to 71.1 +/- 23.1 degrees p =0.01). No immediate or delayed adverse effects related to BoNT/A were noted after the injection. Duration of pain relief was variable and ranged from 3 to 12 months. Five joints were re-injected with IA-Bont/A and had a similar decrease in joint pain that lasted 3 to 12 months. CONCLUSIONS:This is the first report of the long term effects of intra-articular BoNT/A injections to treat chronic joint pain and the efficacy of repeated injections. Although this study was small, and uncontrolled the results suggest that IA-BoNT/A injections are an effective and safe treatment for chronic joint pain disorders. 10.1007/bf03033937
Edgerley Sarah,Zhu Rongbo,Jeimy Samira CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 10.1503/cmaj.201798-f
[Observation on the analgesic effect of heat-reinforcing needling manipulation for acute arthritis and the concomitant changes of beta-EP and PGE2 contents in the local joint tissue in rabbits]. Du Xiao-Zheng,Qin Xiao-Guang,Fang Xiao-Li Zhen ci yan jiu = Acupuncture research OBJECTIVE:To observe the analgesic effect of heat-reinforcing needling manipulation for acute inflammatory arthritis and its underlying mechanism in experimental rheumatoid arthritis rabbits. METHODS:A total of 60 rabbits were randomized into control (n=6), model (n=6), needle-twirling (n=24) and heat-reinforcing (n=24) groups, and the later 2 groups were further divided into 0 h, 0.5 h, 1 h and 2 h subgroups,with 6 cases in each. Rheumatoid arthritis model was established by injecting mixed solution of egg-albumin (4 mg/ml) and equal volume of complete Freund's adjuvant (CFA) into the subcutaneous tissue (6 points around the shoulder, 0.2 ml/point). Fourteen days later,the injection was repeated once again,and another 6 days later, egg-albumin (0.4 ml, 20 mg/ml) solution was injected into the bilateral knee-joints. "Zusanli" (ST 36) and "Hegu" (LI 4) were punctured and stimulated by needle-twirling or by heat-reinforcing needling technique for 1 min, with the needle retained for 30 min. The pain threshold of the paw was detected with K+ import stimulation method. beta-EP and PGE2 contents of the joint tissue were assayed with radioimmunoassay. RESULTS:Compared with model group, the pain threshold of needle-twirling group and heat-reinforcing group at each time-point increased significantly (P<0.01, P<0.05). Compared with needle-twirling group, the pain threshold of heat-reinforcing group at 0.5 h, 1 h and 2 h subgroups increased significantly (P<0.05, P<0.01). Both beta-EP and PGE2 contents of model group were significantly higher than those of control group (P<0.01, P<0.05). In comparison with model group, beta-EP contents of needle-twirling group and heat-reinforcing group at each time-point increased significantly (P<0.01, P<0.05), and PGE2 contents of needle-twirling group and heat-reinforcing group at each time-point decreased significantly (P<0.01, P<0.05). The beta-EP content of heat-reinforcing group was significantly higher than that of needle-twirling group at 2 h (P<0.05), while PGE2 content of the former group was significantly lower than that of needle-twirling group at 0 h (P<0.01). CONCLUSION:Both needle-twirling and heat-reinforcing needling can effectively raise the pain threshold in acute arthritis rabbits, which my be closely associated with their effects in upregulating beta-EP content and lowering PGE2 level in the local joint tissue. The analgesic effect of heat-reinforcing needling manipulation is superior to that of needle-twirling.
Dorsal root reflexes in articular afferents occur bilaterally in a chronic model of arthritis in rats. Rees H,Sluka K A,Lu Y,Westlund K N,Willis W D Journal of neurophysiology 1. Chronic arthritis was produced in rats by the injection of incomplete Freund's adjuvant into one knee joint. By 3-5 days later the rats had developed unilateral swelling of the injected knee and demonstrated bilateral hyperalgesia to radiant heat stimuli applied to the foot. 2. In the same rats anesthetized 3-5 days after the injection, dorsal root reflexes could be recorded bilaterally from the proximal ends of the cut medial articular nerves (MANs) of the knee joint. 3. The dorsal root reflexes consisted of large, medium-sized, and small action potentials evoked in response to phasic mechanical stimulation of the lateral aspect of the knee. The activity was greater in the MAN ipsilateral to the injection than in the contralateral MAN. 4. Local application of capsaicin on the side ipsilateral or contralateral to the arthritis dramatically reduced the dorsal root reflexes recorded from the contralateral MAN, indicating that these dorsal root reflexes depended on activity in fine afferent fibers containing capsaicin receptors, presumably C fibers. Local application of capsaicin on either side did not significantly change the dorsal root reflexes recorded from the ipsilateral MAN. These dorsal root reflexes were presumably conducted in afferent fibers that lacked capsaicin receptors, including A beta- and A delta-fibers. 10.1152/jn.1996.76.6.4190
Fiber types contributing to dorsal root reflexes induced by joint inflammation in cats and monkeys. Sluka K A,Rees H,Westlund K N,Willis W D Journal of neurophysiology 1. Injection of kaolin and carrageenan into the knee joint of cats or monkeys resulted in an acute inflammation. Four hours after injection of the knee joint, efferent activity could be evoked in articular afferent fibers and in dorsal root filaments. We interpret this efferent activity to be dorsal root reflexes (DRRs). Under our experimental conditions, the DRRs were generally synchronized compound action potentials, although in some cases single-unit activity was also observed. 2. DRRs were not produced in animals with uninflamed knee joints and normal body temperatures. 3. Recordings from two different sites on cut dorsal root filaments ipsilateral to the inflamed knee joint allowed the determination of the conduction velocities of groups of afferent fibers carrying DRRs. The DRRs occurred in A beta-, A delta-, and C fibers. However, in these experiments the peripheral destination of the afferent fibers was unknown. 4. To prove that DRRs occurred in joint afferents, recordings were made from two different sites on the proximal stump of the medial articular nerve that innervated the inflamed knee. The DRRs were again found in all fiber types, i.e., group II, III, and IV (A beta, A delta, and C) articular afferent fibers. 5. Compound DRRs were recorded from the central end of a cut dorsal root filament after electrical stimulation at C fiber intensity of a dorsal root adjacent to the filament. This DRR activity was eliminated by extensive dorsal rhizotomies of the L2-S1 roots.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1152/jn.1995.74.3.981
Low-intensity muscle contraction exercise following the onset of arthritis improves hyperalgesia via reduction of joint inflammation and central sensitization in the spinal cord in a rat model. Ishikawa Kumiko,Kajiwara Yasuhiro,Sakamoto Junya,Sasaki Ryo,Goto Kyo,Honda Yuichiro,Kataoka Hideki,Okita Minoru Neuroscience letters We examined the effect of immobilization, low-intensity muscle contraction exercise, and transcutaneous electrical nerve stimulation (TENS) on tissue inflammation and acute pain following the onset of arthritis in a rat model. Sixty Wistar rats were divided into five groups: (1) Arthritis group, (2) arthritis and immobilization (Immobilization group), (3) arthritis and low intensity muscle contraction (Exercise group), (4) arthritis and TENS (TENS group), and (5) sham arthritis (Sham group). Arthritis was induced in the right knee joints by single injection of 3% kaolin and carrageenan. Immobilization of the right hindlimb was conducted by full extension of the right knee joints and full plantar flexion of the ankle joints using a plaster cast for 7 days after injection. The right quadriceps muscles were subjected to electrical stimulation (frequency: 50 Hz; intensity: 2-3 mA) for 20 min/day as contraction exercise for one week. TENS was delivered at 20 min/day for one week (frequency: 50 Hz; intensity: 1 mA). The pressure pain threshold (PPT) and paw withdrawal response (PWR) were evaluated at 1 and 7 days after injection. We also analyzed the number of CD68-positive cells in the synovium by immunohistochemistry and determined the expression level of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn with immunofluorescence. Improvements of both PPT and PWR were observed in the Exercise group at 7 days after injection compared to those of the Arthritis and Immobilization groups, although only improvement of PPT was observed in the TENS group. The number of CD68-positive cells in the synovium and CGRP expression in the dorsal horn decreased only in the Exercise group. These results suggested that low-intensity muscle contraction exercise might be a better treatment for reduction of arthritis-induced inflammation and acute pain compared to immobilization and TENS. 10.1016/j.neulet.2019.04.031
Amygdala group II mGluRs mediate the inhibitory effects of systemic group II mGluR activation on behavior and spinal neurons in a rat model of arthritis pain. Mazzitelli Mariacristina,Neugebauer Volker Neuropharmacology The amygdala plays a critical role in emotional-affective aspects of behaviors and pain modulation. The central nucleus of amygdala (CeA) serves major output functions, and neuroplasticity in the CeA is linked to pain-related behaviors in different models. Activation of G-coupled group II metabotropic glutamate receptors (mGluRs), which consist of mGluR2 and mGluR3, can decrease neurotransmitter release and regulate synaptic plasticity. Group II mGluRs have emerged as targets for neuropsychiatric disorders and can inhibit pain-related processing and behaviors. Surprisingly, site and mechanism of antinociceptive actions of systemically applied group II mGluR agonists are not clear. Our previous work showed that group II mGluR activation in the amygdala inhibits pain-related CeA activity, but behavioral and spinal consequences remain to be determined. Here we studied the contribution of group II mGluRs in the amygdala to the antinociceptive effects of a systemically applied group II mGluR agonist (LY379268) on behavior and spinal dorsal horn neuronal activity, using the kaolin/carrageenan-induced knee joint arthritis pain model. Audible and ultrasonic vocalizations (emotional responses) and mechanical reflex thresholds were measured in adult rats with and without arthritis (5-6 h postinduction). Extracellular single-unit recordings were made from spinal dorsal horn wide dynamic range neurons of anesthetized (isoflurane) rats with and without arthritis (5-6 h postinduction). Systemic (intraperitoneal) application of a group II mGluR agonist (LY379268) decreased behaviors and activity of spinal neurons in the arthritis pain model but not under normal conditions. Stereotaxic administration of LY379268 into the CeA mimicked the effects of systemic application. Conversely, stereotaxic administration of a group II mGluR antagonist (LY341495) into the CeA reversed the effects of systemic application of LY379268 on behaviors and dorsal horn neuronal activity in arthritic rats. The data show for the first time that the amygdala is the critical site of action for the antinociceptive behavioral and spinal neuronal effects of systemically applied group II mGluR agonists. 10.1016/j.neuropharm.2019.107706
Serotonin in an antigen-induced arthritis of the rabbit temporomandibular joint. Tominaga K,Alstergren P,Kurita H,Kopp S Archives of oral biology The aim was to investigate the joint perfusate concentration of serotonin (5-HT) in antigen-induced monoarthritis of the rabbit temporomandibular joint (TMJ) and knee joint. Thirty adult male New Zealand White rabbits, of whom eight were first used as healthy controls, were divided into TMJ and knee arthritis groups. Unilateral arthritis was induced with ovalbumin intra-articularly and the contralateral joint was sham-induced. The joints were perfused with saline (flow rate, 0.05 ml/min; 10-min intervals during 50 min) 3 weeks later and the 5-HT concentration analysed. After the perfusion, the joints were evaluated histologically. The 5-HT concentration in the initial perfusate from the arthritic TMJ was higher than in both sham-induced and healthy control joints, and from the knee joint arthritis higher than in sham-induced joints. No histological difference in the arthritis was observed between the two groups. This study shows that the 5-HT concentration found immediately after puncture is increased in antigen-induced arthritis of the rabbit TMJ and knee joint. 10.1016/s0003-9969(99)00026-6
The role of substance P in microvascular responses in murine joint inflammation. Keeble Julie,Blades Mark,Pitzalis Costantino,Castro da Rocha Fransisco Airton,Brain Susan Diana British journal of pharmacology 1. Rheumatoid arthritis is a serious, inflammatory disease of the distal joints that has a possible neurogenic component underlying its pathology. 2. Substance P (SP), an endogenous neuropeptide that acts upon the neurokinin 1 (NK(1)) receptor, is released from sensory nerves and is involved in neurogenic inflammation. 3. In this study, we have developed novel techniques to determine the contribution of SP to microvascular responses in a model of complete Freund's adjuvant (CFA)-induced arthritis in NK(1) knockout mice. 4. Detailed analysis in normal mice revealed that CFA (20 microg i.art.)-induced plasma extravasation was raised from 18 to 72 h, when compared with intravascular volume. By comparison, knee swelling was sustained for 3 weeks. Neutrophil accumulation mirrored plasma extravasation. SP (10 pmol i.art.) caused significant acute plasma extravasation, but not other parameters, in wild type (WT), but not NK(1) knockout mice. CFA (10 microg i.art.) induced a significantly decreased intravascular volume, presumably due to decreased blood flow, at early time points (5 and 7 h) in WT but not NK(1) knockouts. Otherwise, similar responses in WT and NK(1) knockout mice were observed. However, injection of SP into CFA-pretreated joints caused a significant enhancement of plasma extravasation and knee swelling in the WT but not NK(1) knockouts. 5. In conclusion, the present study has used novel techniques in WT and NK(1) knockout mice to show that SP can modulate vascular tone and permeability in the inflamed joint via activation of the NK(1) receptor and that SP-induced responses are more pronounced where pre-existing inflammation is present. 10.1038/sj.bjp.0706131
Involvement of substance P and neurokinin-1 receptors in the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint. Neugebauer V,Weiretter F,Schaible H G Journal of neurophysiology 1. In anesthetized rats we studied the involvement of substance P and neurokinin-1 receptors in the generation and maintenance of hyperexcitability in spinal cord neurons, which develops in the course of an acute experimental inflammation in the knee. In all experiments one nociceptive neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the injections of kaolin and carrageenan into the knee joint. In 18 experiments either the specific antagonist at the neurokinin-1 receptor ionophoretically close to the neuron or intravenously during the injections of kaolin and carrageenan and in three periods of 15 min in the 95 min postkaolin (initial period of inflammation) to test their effects on the development of hyperexcitability. CP96,345 and CP96,344 were also administered after full development of inflammation to study their effects in hyperexcitable neurons. CP96,345 was ejected at currents that reduced or completely suppressed the effects of ionophoretically administered substance P but not those of neurokinin A, the agonist at neurokinin-2 receptors. 2. After the injections of kaolin and carrageenan into the knee joint, untreated control neurons (n = 8) developed hyperexcitability consisting of enhanced responses to noxious stimuli applied to the injected knee and the noninjected ankle, of an enhancement or induction of the responses to innocuous pressure applied to the joints and of an expansion of the receptive field. In eight neurons treated with ionophoretic administration of CP96,345 during the induction and initial period of inflammation, the development of hyperexcitability was not completely prevented but significantly attenuated. In comparison with the changes in the control neurons, the development of hyperexcitability was markedly reduced from the 2nd h up to 5 h postkaolin, but it was barely affected by CP96,345 within the 1st h postkaolin. Intravenous administration of CP96,345 in the initial period of inflammation produced a similar reduction of the development of hyperexcitability in another four neurons. The ionophoretic application of CP96,344 during and after induction of inflammation did not apparently impair the development of hyperexcitability (n = 6 neurons). 3. After development of inflammation and hyperexcitability, both the responses to innocuous and noxious pressure applied to the inflamed knee joint were reduced by the ionophoretic (n = 16 neurons) and intravenous administration (n = 9 neurons) of CP96,345 (tested 4.5-8 h postkaolin). Similarly, the responses to innocuous and noxious pressure applied to the noninflamed ankle were reduced by CP96,345 after inflammation had developed in the knee joint.(ABSTRACT TRUNCATED AT 400 WORDS) 10.1152/jn.1995.73.4.1574
The role of spinal neurokinin-2 receptors in the processing of nociceptive information from the joint and in the generation and maintenance of inflammation-evoked hyperexcitability of dorsal horn neurons in the rat. Neugebauer V,Rumenapp P,Schaible H G The European journal of neuroscience In spinal cord neurons in anesthetized rats, the role on neurokinin A and neurokinin-2 receptors in the processing of nociceptive information from the knee joint was studied. The specific non-peptide antagonist at the neurokinin-2 receptor, SR48968, its inactive R-enantiomer, SR48965, neurokinin A, substance P and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), were administered ionophoretically close to neurons with input from the knee joint. SR48968 reduced the effects of exogenous neurokinin A, but not those of exogenous substance P and AMPA, indicating selective blockade of neurokinin-2 receptors. In most neurons with input from the normal knee joint, SR48968 reduced dose-dependently the responses to noxious pressure with applied to the knee, and in approximately 50% of the neurons the responses to innocuous pressure. The administration of SR48968 during the induction of an experimental joint inflammation markedly attenuated the development of inflammation-evoked hyperexcitability. In hyperexcitable neurons with input from the inflamed joint, SR48968 reduced the responses to noxious and innocuous pressure. The relative reduction of the responses was more pronounced than in neurons with input from the normal joint. None of the effects of SR48968 was mimicked by SR48965. These data show that neurokinin-2 receptors are involved in the spinal processing of nociceptive information from the normal joint. Furthermore, neurokinin-2 receptors must be coactivated at an early stage of inflammation, to allow the generation of hyperexcitability. Finally, neurokinin-2 receptors are involved in maintenance of hyperexcitability during inflammation. In summary, spinal neurokinin-2 receptors are important in the generation of pain in the normal and inflamed joint.
The role of acupuncture in pain management. Audette Joseph F,Ryan Angela H Physical medicine and rehabilitation clinics of North America This article reviews the theories and applications of acupuncture to musculoskeletal pain management. First, Chinese theories of acupuncture are discussed briefly. Next, current understanding of nociception and central pain modulation is discussed in detail,followed by discussion of the physiologic effect of acupuncture analgesia. Other theories of acupuncture analgesia are presented based on neuromodulation of the central nervous system. Finally,the efficacy of acupuncture for many musculoskeletal pain syndromes,including spine-related pain, soft tissue pain, neuropathic pain, arthritis of the knee, and upper extremity tendinitis, is reviewed. The article concludes with a discussion of methodologic issues related to conducting randomized, placebo-controlled trials of acupuncture and goals for future research in this area of pain management. 10.1016/j.pmr.2004.03.009
Monoarthritis in the rat knee induces bilateral and time-dependent changes in substance P and calcitonin gene-related peptide immunoreactivity in the spinal cord. Mapp P I,Terenghi G,Walsh D A,Chen S T,Cruwys S C,Garrett N,Kidd B L,Polak J M,Blake D R Neuroscience Bilateral changes in the spinal cord and dorsal root ganglion content of the sensory peptides substance P and calcitonin gene-related peptide have been previously reported in animal models of arthritis which affect many joints within the body. The central nervous system has been implicated in the symmetry of joint involvement in human rheumatoid arthritis. We aimed to determine whether unilateral inflammation of the knee joint can also induce bilateral changes in the spinal cord. We have induced a monoarthritis in the knee joint of the rat and used quantitative immunocytochemistry to look at changes of these peptides in the dorsal horn of the spinal cord and the dorsal root ganglia. Furthermore we have examined the responses during the acute (three days) and the chronic (21 days) phases of the model. The data show that in the acute phase of the monoarthritis there is both an ipsilateral and contralateral response which increases the immunoreactive substance P and calcitonin gene-related peptide in the L4 level of the dorsal horn of the spinal cord. In the chronic phase of the monoarthritis, the contralateral side of the dorsal horn returned to control values whilst the ipsilateral side showed reduced amounts of immunoreactive substance P and calcitonin gene-related peptide compared to controls. We propose that the acute response, at three days, to unilateral inflammation is appropriate and has evolved to protect an organism against the original insult ipsilaterally, and the possibility of subsequent insult contralaterally.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1016/0306-4522(93)90051-g
Effect of brain-derived neurotrophic factor on the release of substance P from rat spinal cord. Meyer-Tuve A,Malcangio M,Ebersberger A,Mazario J,Schaible H G Neuroreport Brain-derived neurotrophic factor (BDNF) can produce hyperalgesia in the adult rat. Here we assessed whether changes in the spinal release of the nociceptive peptide substance P (SP) contributes to this effect. Antibody-coated microprobes revealed a significant basal release of SP in the dorsal horn in vivo that was increased following acute knee inflammation. Microinjection of BDNF into the grey matter (0.5 microl, 10(-5) M) altered SP release neither in rats with normal knees nor in rats with inflamed knee joints. In the lumbar dorsal horn slice preparation in vitro, superfusion with BDNF (100 ng/ml) could reduce SP release evoked by electrical dorsal root stimulation without modyfing SP basal outflow. It is unlikely, therefore, that enhanced spinal SP release mediates the hyperalgesic effect of BDNF. 10.1097/00001756-200101220-00012
Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat. Green P G,Basbaum A I,Helms C,Levine J D Proceedings of the National Academy of Sciences of the United States of America We assessed the contribution of ATP and adenosine (i) to a major sign of acute inflammation, plasma extravasation (PE), in the rat knee joint and (ii) to the severity of joint injury in adjuvant-induced experimental arthritis, a chronic inflammatory disease. PE induced by local infusion of bradykinin, which we have previously shown to depend on the sympathetic postganglionic neuron terminal, was markedly enhanced by coinfusion of either ATP or the adenosine A2-receptor agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine. Bradykinin-induced PE was inhibited by coinfusion of the ATP receptor antagonist adenosine 5'-[alpha,beta-methylene]triphosphate, the A2-receptor antagonist 3-(5H-thiozolo[2,3b]quinazolin-3-yl)phenol monohydrochloride, or the adenosine A1-receptor agonist N6-cyclopentyladenosine. The joint injury associated with experimental arthritis, which is reduced in severity in sympathectomized rats, was also markedly attenuated by daily administration of either ATP (40% reduction) or adenosine (55% reduction). These results demonstrate that the purines ATP and adenosine (acting at the A2 receptor), cotransmitters in the sympathetic postganglionic neuron terminal, enhance bradykinin-induced sympathetic postganglionic neuron terminal-dependent PE but inhibit the joint injury of arthritis. These opposing purinergic effects on PE and joint injury suggest that enhanced PE protects against joint injury. 10.1073/pnas.88.10.4162
Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats. DeSantana Josimari M,da Silva Luis Felipe S,Sluka Kathleen A Pain Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100Hz) or low frequency (4Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner. 10.1016/j.pain.2009.10.011
Capsaicin-induced vasoconstriction in the mouse knee joint: a study using TRPV1 knockout mice. Keeble Julie Elizabeth,Brain Susan Diana Neuroscience letters Capsaicin is the pungent component of chilli peppers that concomitantly activates and desensitizes C-fibre and Adelta sensory nerve fibres. Stimulation causes an acute neurogenic response including vasodilation, plasma extravasation and hypersensitivity. However, in the present study we have shown that capsaicin produces a dose-dependent vasoconstrictor effect in the mouse knee joint via Transient Receptor Potential Vanilloid 1 (TRPV1) receptor activation. A (125)I-albumin accumulation technique showed that the intravascular volume of capsaicin-treated joints in wild type (WT) mice was significantly reduced compared to TRPV1 knockout mice (p<0.01). Similarly, a laser Doppler technique showed significantly reduced blood flow in the capsaicin-treated joints of WT compared to TRPV1 knockout mice (p<0.001). Pretreatment with guanethinidine (50 mg kg(-1), i.p.) had no effect on the vasoconstriction. These data are important considering the involvement of TRPV1 receptors in joint disease. The mechanisms underlying the vasoconstriction therefore require further investigation. 10.1016/j.neulet.2006.02.083
Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Molecular pain BACKGROUND:Arthritis pain is an important healthcare issue with significant emotional and affective consequences. Here we focus on potentially beneficial effects of activating small-conductance calcium-activated potassium (SK) channels in the amygdala, a brain center of emotions that plays an important role in central pain modulation and processing. SK channels have been reported to regulate neuronal activity in the central amygdala (CeA, output nucleus). We tested the effects of riluzole, a clinically available drug for the treatment of amyotrophic lateral sclerosis, for the following reasons. Actions of riluzole include activation of SK channels. Evidence in the literature suggests that riluzole may have antinociceptive effects through an action in the brain but not the spinal cord. Mechanism and site of action of riluzole remain to be determined. Here we tested the hypothesis that riluzole inhibits pain behaviors by acting on SK channels in the CeA in an arthritis pain model. RESULTS:Systemic (intraperitoneal) application of riluzole (8 mg/kg) inhibited audible (nocifensive response) and ultrasonic (averse affective response) vocalizations of adult rats with arthritis (5 h postinduction of a kaolin-carrageenan monoarthritis in the knee) but did not affect spinal withdrawal thresholds, which is consistent with a supraspinal action. Stereotaxic administration of riluzole into the CeA by microdialysis (1 mM, concentration in the microdialysis fiber, 15 min) also inhibited vocalizations, confirming the CeA as a site of action of riluzole. Stereotaxic administration of a selective SK channel blocker (apamin, 1 µM, concentration in the microdialysis fiber, 15 min) into the CeA had no effect by itself but inhibited the effect of systemic riluzole on vocalizations. Off-site administration of apamin into the basolateral amygdala (BLA) as a placement control or stereotaxic application of a selective blocker of large-conductance calcium-activated potassium (BK) channels (charybdotoxin, 1 µM, concentration in the microdialysis fiber, 15 min) into the CeA did not affect the inhibitory effects of systemically applied riluzole. CONCLUSIONS:The results suggest that riluzole can inhibit supraspinally organized pain behaviors in an arthritis model by activating SK, but not BK, channels in the amygdala (CeA but not BLA). 10.1186/s12990-015-0055-9
An experimental arthritis model in rats: the effects of NMDA and non-NMDA antagonists on aspartate and glutamate release in the dorsal horn. Sluka K A,Westlund K N Neuroscience letters Release of excitatory amino acids (EAA's) in the dorsal horn of awake rats was monitored by microdialysis during the development of arthritis induced by injection of 3% kaolin and 3% carrageenan into the knee joint. Concentrations of EAA's in the dialysate samples were measured by high performance liquid chromatography at baseline, during delivery of EAA antagonists, and for the first 8 h of arthritis. An initial increase in aspartate (ASP) and glutamate (GLU) was observed on injection of the knee joint in rats made arthritic. Subsequently, there was a prolonged release phase after 3 h which persisted at least 8 h. Specific EAA antagonists to non-N-methyl-D-aspartate (non-NMDA; CNQX) and to NMDA (AP7) receptors were used to block the effects seen in the untreated arthritic animals. The increase in ASP and GLU release seen at the time of injection in untreated arthritic animals did not occur in arthritic animals treated with EAA receptor antagonists (CNQX or AP7). In arthritic animals treated with CNQX, the prolonged release phase was delayed and attenuated for GLU and decreased below baseline for ASP. In the AP7-treated arthritic animals, no change from baseline concentration was observed for ASP until 7 h, and GLU decreased minimally. The data indicate that this arthritis model is accompanied by an initial increased release of EAA's at the time of injection which is dependent on the activation of both non-NMDA and NMDA receptors. Subsequent development of arthritis, manifested as an inflamed joint and a delayed and prolonged release of ASP and GLU, is dependent on the initial activation of these EAA receptors.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1016/0304-3940(93)90357-q
Are neuropeptides important in arthritis? Studies on the importance of bombesin/GRP and substance P in a murine arthritis model. Grimsholm O,Guo Yz,Ny T,Rantapää-Dahlqvist S,Forsgren S Annals of the New York Academy of Sciences Interference with the effects of neuropeptides may be of potential therapeutic value for the treatment of rheumatoid arthritis (RA). Two neuropeptides that can be discussed in this context are bombesin/gastrin-releasing peptide (BN/GRP) and substance P (SP). In order to obtain new information on the possible importance of these two peptides, the patterns of immunohistochemical expression of BN/GRP and SP and their related receptors in the mouse knee joint from healthy and arthritic mice were examined. Positive staining for GRP receptor and the SP preferred receptor (the neurokinin-1 receptor [NK-1 R]) was observed in articular chondrocytes. On the whole, there was a decrease in immunoreactions for both the GRP- and the NK-1 receptors in the articular chondrocytes in joints exhibiting severe arthritis. Staining for BN/GRP and GRP receptor was seen in the inflammatory infiltrates of the arthritic joints. New evidence for the occurrence of marked effects of BN/GRP concerning both the articular chondrocytes and the inflammatory process is obtained in this study. With these findings and previous observations of neuropeptide expression patterns and functions we discuss the possibility that interventions with the effects of BN/GRP, SP, and other neuropeptides might be worthwhile in RA. 10.1196/annals.1423.056
Effects of All-Trans Retinoic Acid on Lipopolysaccharide-Induced Synovial Explant. Lu Kuiqing,Bao Qilin,Wang Dan,Ning Yanhua,Xie Xuejian,Zhou Mingming,Zhou Linhua,Zeng Xiang,Shan Jingyan,Li Yun Journal of nutritional science and vitaminology The present study was conducted to assess the effect of all-trans retinoic acid (ATRA) on synovial explants from rats with rheumatoid arthritis (RA) induced by lipopolysaccharides (LPS). In our study, synovial membranes were excised from the knees of healthy adult Wistar female rats under sterile conditions. We first investigated the synoviums incubated in a control medium or in a medium containing 10 μg/mL LPS, each for 24, 48, and 72 h (LPS-experiment). The changes in inflammatory response from the synoviums were observed at different culture times. Then, we assessed the synoviums exposed to different ATRA concentrations for 24 h (ATRA-experiment). The controls (blank, model group, and solvent groups) were set up. The effects of ATRA on synovitis were evaluated by measuring the production of cytokines, and nitric oxide (NO) and the expression of cartilage damage related proteases. In the LPS-experiment, LPS contributed to the release of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) in synovial explants. Importantly, LPS did not cause a significant pathological damage. The inflammatory response observed in this model was significant for 24 h, suggesting that LPS-induced synovial explants were successfully established. In the ATRA-experiment, ATRA suppressed the expression of IL-6, TNF-α, NO, a disintegrin and metalloprotease with thrombospondin motifs-4 (ADAMTS-4), MMP-3, and MMP-9. Taken together, ATRA exhibited inhibitory effects on LPS-induced synovial immune inflammatory response stimulated by the regulation of inflammatory mediators and cartilage damage related proteases in synovial explants, demonstrating a potential protective effect on synovitis and joint destruction in the patients with RA. 10.3177/jnsv.65.8
Spatial variation in sympathetic influences on the vasculature of the synovium and medial collateral ligament of the rabbit knee joint. McDougall J J,Ferrell W R,Bray R C The Journal of physiology 1. Laser Doppler perfusion imaging was used to assess the role of the sympathetic nervous system in the control of blood flow to the medial collateral ligament and capsule (synovium and overlying fibrous tissues) of the rabbit knee joint. 2. Electrical stimulation of the saphenous nerve (width 1 ms; amplitude 20V; 1-30 Hz) produced a frequency-dependent vasoconstriction of knee joint vasculature. The response was maximal at 30 Hz and gave the greatest fall in perfusion at the femoral insertion of the ligament (by 33.8 +/- 7.4%, mean +/- S.E.M.; n = 5-6) and the smallest decrease at the tibial insertion of the ligament (by 10.6 +/- 2.9%). 3. Topical application of phentolamine (10(-6) mol) had no significant effect on basal knee joint blood flow. However, it abolished the nerve-mediated constrictor responses in all regions of the medial collateral ligament and synovium at all frequencies. 4. Topical administration of adrenaline (10(-14) to 10(-7) mol) caused a dose-dependent decrease in knee joint blood flow with the highest dose producing > 75% reduction in perfusion at all areas. 5. There was no evidence of a reactive hyperaemia in the 5 min following a 5 min period of femoral artery occlusion. Artificial manipulation of arterial blood pressure by intravenous infusion or withdrawal of blood caused a proportional change in ligament and synovial blood flow. These observations may indicate a lack of autoregulation in the joint and its exclusion from baroreflex modulation. 6. These results suggest a potential role for the sympathetic nervous system in the control of knee joint blood flow. Neuromodulation of ligament perfusion appears to predominate at the femoral insertion and this could prove to have functional significance. 10.1111/j.1469-7793.1997.435bh.x
Role of nitric oxide in the inhibition of BMP-2-mediated stimulation of proteoglycan synthesis in articular cartilage. van der Kraan P M,Vitters E L,van Beuningen H M,van de Loo F A,van den Berg W B Osteoarthritis and cartilage OBJECTIVE:Bone morphogenetic protein-2 (BMP-2)-mediated stimulation of articular cartilage proteoglycan (PG) synthesis is suppressed in arthritic murine knee joints and by interleukin-1 (IL-1). The goal of this study was to investigate whether the gaseous mediator nitric oxide (NO) plays a crucial role in the inhibition of BMP-2 effects by IL-1. METHODS:Bone morphogenetic protein-2 alone or in combination with IL-1 was injected into the right knee joint of wild-type and NOS2 deficient C57BI/6x129/Sv mice. Proteoglycan synthesis was measured ex vivo by incorporation of 35S-sulfate on day 1, 2 and 3 after injection. To study the role of NO in the inhibition BMP-2-mediated stimulation of PG synthesis in arthritic joints, BMP-2 was injected intra-articularly in the joints of wild-type and NOS2 deficient mice with zymosan-induced arthritis. To check for NOS2 deficiency, NO production was measured in conditioned medium after challenge of patellae with surrounding tissue with IL-1. RESULTS:BMP-2 potently stimulated proteoglycan synthesis in articular cartilage of normal knees (up to 4-fold) but not in arthritic knees. Co-injection of BMP-2 with tumor necrosis factor alpha had no effect on BMP-2-mediated stimulation of PG synthesis but co-injection with IL-1 alpha resulted in a nearly total inhibition of BMP-2-mediated stimulation. In contrast, in NOS2 deficient mice IL-1 had no effect on BMP-2-mediated stimulation of PG synthesis. However, injection of BMP-2 into arthritic knee joints of NOS2 knock out mice did not result in significant stimulation of PG synthesis. CONCLUSIONS:In this study we show that NO plays a role in the inhibition of BMP-2-mediated stimulation of PG synthesis by IL-1. However, NO, or at least NOS2, plays no dominant role in the inhibition of BMP-2 effects in arthritic knee joints. 10.1053/joca.1999.0275
Effect of pyrimethamine in experimental rheumatoid arthritis. Saadat Farshid,Cuzzocrea Salvatore,Di Paola Rosanna,Pezeshki Mohammad,Khorramizadeh Mohammad Reza,Sedaghat Mohammad,Razavi Alireza,Mirshafiey Abbas Medical science monitor : international medical journal of experimental and clinical research BACKGROUND:Recent evidence has shown that the antimalarials are useful drugs in the treatment of various rheumatic diseases. The present study was designed to test the therapeutic effect of pyrimethamine (PYR) in collagen-induced arthritis (CIA). MATERIAL/METHODS:CIA was induced in Lewis rats. The intraperitoneal administration of PYR and methotrexate (MTX) were started on day 25 post-immunization and continued until final assessment on day 35. During this period, clinical examination was performed intermittently. Anti-C II Ab and nitric oxide (NO) synthesis were measured. The paws and knees were then removed for histopathology and radiography assay. The biocompatibility of PYR and MTX were assessed using a fibrosarcoma cell line. RESULTS:Data showed that i.p. injection of pyrimethamine to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cell infiltrate in the joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following PYR therapy. Moreover, our radiography results paralleled our histological findings. Cytotoxicity analysis of PYR showed greater tolerability compared with MTX. Treatment with PYR significantly diminished nitric oxide formation in treated rats compared with untreated controls. CONCLUSIONS:Our findings shed light on the therapeutic efficacy of pyrimethamine in experimental rheumatoid arthritis compared with a choice drug (methotrexate), which may recommended it as a second-line drug in the treatment of rheumatoid arthritis.
Neurovascular plasticity in the knee joint of an arthritic mouse model. Buma P,Elmans L,Van Den Berg W B,Schrama L H The Anatomical record Lower numbers of neuropeptide-containing fibers in arthritic joints have been found as compared to control joints. This may be the result of fiber depletion, necrosis of fibers, or proliferation of soft tissues without neural sprouting. To discriminate between these possibilities, we studied the relationships between soft tissue proliferation, changes in vascularity of synovial tissues, and changes in joint innervation during arthritis. Arthritis was induced in the knee joint of mice by a single subpatellar injection of methylated bovine serum albumin after previous immunization. Antibodies to protein gene product 9.5, S-100, and growth-associated protein-43 (GAP-43) were used to study the general innervation pattern. Antibodies to calcitonin gene-related peptide (CGRP), vasointestinal polypeptide (VIP), substance P (SP), and tyrosine hydroxylase (TH) were used to localize sensory (SP, CGRP, VIP) and sympathetic (TH) fibers. Blood vessels of the joint were studied with ink perfusion, GAP-43, and a vascular marker (LF1). Directly after the induction of arthritis, the synovial cavity was enlarged and filled with leukocytes. From day 4 onward, small sprouting blood vessels penetrated the avascular mass of cells in the joint cavity. After 1 week, the vascular sprouting activity and GAP-43 immunoreactivity were maximal, and after 2 weeks, vascular sprouting activity diminished. In the subsequent period, the synovia slowly regained their prearthritic appearance and thickness. The most pronounced changes in the general staining pattern of CGRP, SP, VIP, and TH were found in the periosteum. From 2 days to 4 weeks after the induction of arthritis, the layer of SP, CGRP, and VIP fibers in the femoral periosteum was thicker and more irregular. GAP-43 staining showed many terminal varicosities, which suggested sprouting of nerve fibers. From 2 days to 2 weeks after the induction of arthritis, the SP and CGRP fibers in the periosteum showed gradual depletion. In the thickened subsynovial tissues that were revascularized, no ingrowth of neural elements was found. As the total number of nerve fibers in the synovial tissue did not change, large parts of the synovia directly facing the joint cavity were not innervated at 1 week after the induction of arthritis. These results strongly suggest that periosteal SP and CGRP fibers were depleted during arthritis. Synovial proliferation without concomitant fiber growth is the main cause of the reduced number of immunocytochemically detectable fibers in the mouse arthritic knee joint. 10.1002/1097-0185(20000901)260:1<51::AID-AR60>3.0.CO;2-9
Increased intra-articular substance P and prostaglandin E2 following injection of interleukin-1 in rabbits. O'Byrne E M,Blancuzzi V J,Wilson D E,Wong M,Peppard J,Simke J P,Jeng A Y International journal of tissue reactions Inflammation was induced by intra-articular injection of 100 ng recombinant human interleukin-1 alpha (rhIL-1) into rabbit knees. Substance P (SP) and prostaglandin E2 (PGE2) were measured by radioimmunoassay (RIA) in the joint fluid at 4, 24 and 48 h after rhIL-1 injection. SP was increased by 4 h, further increased at 24 h and remained elevated at 48 h. PGE2 concentration was highest at 4 h and remained elevated at 48 h after rhIL-1 injection. Because of the proinflammatory activities of SP and PGE2, our studies suggest that the elevated SP and PGE2, in the joint may amplify or sustain an initial receptor-mediated inflammatory response to IL-1.
Acute inflammation enhances substance P-induced plasma protein extravasation in the rat knee joint. Scott D T,Lam F Y,Ferrell W R Regulatory peptides Acute inflammation of the rat knee joint was induced by intra-articular injection of 2% carrageenan. Intra-articular perfusion of the inflamed joint with substance P (SP) exacerbated the inflammatory condition as assessed by the degree of plasma protein extravasation into the synovial cavity. Protein extravasation induced by SP was enhanced and more persistent in the inflamed rat knee compared to normal animals. The time course of the response in the inflamed rat knee was related to SP concentration whilst the persistency of the response was positively correlated with the initial level of joint inflammation.
Release and spread of immunoreactive neurokinin A in the cat spinal cord in a model of acute arthritis. Hope P J,Jarrott B,Schaible H G,Clarke R W,Duggan A W Brain research Antibody microprobes were used to study the release of immunoreactive neurokinin A into the spinal cord of anaesthetised cats during and following injection of a knee joint with kaolin and carrageenan. A basal level of immunoreactive neurokinin A was detected prior to any noxious stimuli. Innocuous mechanical joint stimuli (flexion or pressure) did not alter this basal level of release. However, on injection of kaolin and carrageenan into a knee joint, evidence of release into the ipsilateral spinal cord was immediately observed. Initially, immunoreactive neurokinin A was detected in 2 regions: one at the dorsal surface of the spinal cord and the other centred on the superficial dorsal horn. Within 1 h of joint injection, however, immunoreactive neurokinin A was detected throughout the dorsal horn and the adjacent white matter. The extensive spread and persistence of immunoreactive neurokinin A in the spinal cord may underlie some of the prolonged excitability changes evoked by brief noxious stimuli and peripheral inflammation reported by other laboratories. 10.1016/0006-8993(90)91352-h
The actions of cimetidine hydrochloride and mepyramine maleate in rat adjuvant arthritis. Al-Haboubi H A,Zeitlin I J European journal of pharmacology Adjuvant arthritis in rats was induced by a single subcutaneous injection of Freund adjuvant into a hind paw. The injected paws' mean volume increased continuously by 80 +/- 26% after 6 h (acute local response). The injected paw displayed a biphasic response peaking at day 1-2 decreasing to day 5, then increased to day 14 by 123% while the contralateral non-injected paw showed little increase until day 10 and increased by 42% at day 14. The lateral diameter of both knee-joints also increased biphasically, peaking at day 4, decreasing to day 6, then increasing to day 14 (early and late systemic phase). Mepyramine maleate, 1 mg.kg-1 (i.p.) daily, suppressed only the early systemic phase by 50%. Daily cimetidine hydrochloride, 1 mg.kg -1.day-1, almost completely abolished the inflammatory response in the knee joints up to day 12, while at day 14 the suppression was 71%. The increase in mean paw volume was also suppressed by orally administered cimetidine. Intraperitoneal doses of cimetidine (3.5 mumol.kg-1) totally suppressed paw oedema produced by subplantar injection of histamine (1.8 mM) but had no action on equiactive dose of the specific H1-agonist, 2-pyridylethylamine. Mepyramine at 3.5 mumol.kg-1 or greater produced no more than 50% suppression of the histamine response. A component of both adjuvant and histamine-induced responses thus appears to be histamine H2-receptor mediated. 10.1016/0014-2999(82)90234-5
Joint nociceptor nerve activity and pain in an animal model of acute gout and its modulation by intra-articular hyaluronan. Pain The mechanisms whereby deposition of monosodium urate (MSU) crystals in gout activates nociceptors to induce joint pain are incompletely understood. We tried to reproduce the signs of painful gouty arthritis, injecting into the knee joint of rats suspensions containing amorphous or triclinic, needle MSU crystals. The magnitude of MSU-induced inflammation and pain behavior signs were correlated with the changes in firing frequency of spontaneous and movement-evoked nerve impulse activity recorded in single knee joint nociceptor saphenous nerve fibers. Joint swelling, mechanical and cold allodynia, and hyperalgesia appeared 3 hours after joint injection of MSU crystals. In parallel, spontaneous and movement-evoked joint nociceptor impulse activity raised significantly. Solutions containing amorphous or needle-shaped MSU crystals had similar inflammatory and electrophysiological effects. Intra-articular injection of hyaluronan (HA, Synvisc), a high-MW glycosaminoglycan present in the synovial fluid with analgesic effects in osteoarthritis, significantly reduced MSU-induced behavioral signs of pain and decreased the enhanced joint nociceptor activity. Our results support the interpretation that pain and nociceptor activation are not triggered by direct mechanical stimulation of nociceptors by MSU crystals, but are primarily caused by the release of excitatory mediators by inflammatory cells activated by MSU crystals. Intra-articular HA decreased behavioral and electrophysiological signs of pain, possibly through its viscoelastic filtering effect on the mechanical forces acting over sensitized joint sensory endings and probably also by a direct interaction of HA molecules with the transducing channels expressed in joint nociceptor terminals. 10.1097/j.pain.0000000000001137
Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation. Sluka K A,Milton M A,Willis W D,Westlund K N British journal of pharmacology 1. Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. 3. Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.01-10 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.01-1 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 4. Pretreatment systemically with the NK1 receptor antagonist (30 mg kg-1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg-1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 5. Post-treatment systemically with either the NK1 (0.1-30 mg kg-1) or the NK2 (0.1-10 mg kg-1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. 6. Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 7. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia. 8. Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation. 10.1038/sj.bjp.0701044
Experimental arthritis in rats induced by intra-articular injection of IgE aggregates: evidence for arthritogenic role of complexed IgE. Annals of the rheumatic diseases An experimental arthritis model in the rat was used to study the arthritogenic potential of complexed IgE. IgE aggregates were produced in vitro by cross linking monoclonal rat IgE by dimethyl suberimidate and were injected into the knee joints. Animals which had not been injected and animals injected with phosphate buffered saline served as controls. The concentration of histamine in tissues, diffusion into the joint of bovine serum albumin labelled with iodine-125 injected intravenously, and the histology of the joints were studied. There was a significant decrease in the concentration of histamine in synovial tissue 8 and 24 hours after the injection of the IgE aggregates. A decreased number of stainable mast cells were found 8, 24, and 48 hours after exposure. A moderate hyperplasia of the synovial lining layer was also noted. These results provide further evidence for the arthritogenic potential of complexed IgE, especially in the initiation of arthritis through activation of mast cells. 10.1136/ard.51.2.210
The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis. Blanshan Nicole,Mahowald Maren L,Dorman Christopher,Frizelle Sandra,Krug Hollis E Toxicon : official journal of the International Society on Toxinology PURPOSE:We previously reported the efficacy of intraarticular (IA) rimabotulinumtoxinB (BoNT/B) in a murine model of chronic degenerative arthritis pain. This study aimed to measure the analgesic effects of onabotulinumtoxinA (BoNT/A) on collagenase induced chronic degenerative arthritis joint pain. METHODS:Chronic degenerative arthritis was produced by IA injection of 10 μl collagenase (Col) (10 IU) into the left knee of C57BL/6J female mice 4 weeks prior to pain assessment. IA BoNT/A was injected 3 days before testing. Arthritis pain was measured as evoked pain scores (EPS) and spontaneous pain behaviors with an advanced dynamic weight bearing (ADWB) device. EPS was a tally of fights and vocalizations exhibited in one minute with knee palpation. Percent body weight and percent time spent on each limb was quantified. All mice were 12 weeks old at the time of examination. RESULTS:IA Col increased EPS and reduced ADWB measures of percent weight bearing on the left hind limb compared to naïve mice. BoNT/A treatment reduced EPS and increased weight bearing on the left hind limb. The improvements were not significant compared to the Col group. There was no significant difference in time spent on the left hind limb between any treatment groups. Forelimb ADWB measures of percent weight and time in arthritic mice significantly increased compared to nonarthritic animals. Treatment with BoNT/A in the arthritic limb decreased this offloading; however, statistical analysis only showed significance in weightbearing. CONCLUSION:IA Col monoarthritis increased evoked and spontaneous pain behaviors in female mice after four weeks. Treatment with IA BoNT/A decreased pain behaviors but only forelimb weight bearing showed a significant improvement. This led us to conclude that treatment with BoNT/A is not an effective analgesic for the treatment of chronic degenerative knee arthritis in murine models. 10.1016/j.toxicon.2018.11.307
[A case of limb-girdle type myasthenia gravis in whom rheumatoid arthritis appeared immediately after thymectomy]. Araki E,Yamada T,Imaiso Y,Hara H,Kira J Rinsho shinkeigaku = Clinical neurology We report a 48-year-old female who presented limb-girdle type myasthenia gravis with inflammatory lung lesions and rheumatoid arthritis. She demonstrated a rapidly progressive muscle weakness of extremities. Neurological examination revealed facial muscle weakness, and proximal dominant limb muscle atrophy and weakness. Ptosis, ophthalmoplegia, and bulbar palsy were not observed. The edrophonium test and serum anti-acetylcholine receptor antibody were positive. The repetitive nerve stimulation showed 55% waning in the thenar muscles. From these findings, she was diagnosed as having myasthenia gravis. Plain chest X-P and body CT showed tumor-like lesions in the lung. Lung biopsy revealed the infiltration of lymphocytes. These lesions decreased in size after thymectomy and corticosteroid administration. Immediately after thymectomy, she began to have morning stiffness with pain and swelling of the finger and knee joints. RAHA test, which was negative before thymectomy, became highly positive. These findings were consistent with rheumatoid arthritis. In this patient, thymus probably played a role to suppress the development of rheumatoid arthritis.
Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats. DeSantana J M,Da Silva L F S,De Resende M A,Sluka K A Neuroscience Transcutaneous electric nerve stimulation (TENS) is widely used for the treatment of pain. TENS produces an opioid-mediated antinociception that utilizes the rostroventromedial medulla (RVM). Similarly, antinociception evoked from the periaqueductal grey (PAG) is opioid-mediated and includes a relay in the RVM. Therefore, we investigated whether the ventrolateral or dorsolateral PAG mediates antinociception produced by TENS in rats. Paw and knee joint mechanical withdrawal thresholds were assessed before and after knee joint inflammation (3% kaolin/carrageenan), and after TENS stimulation (active or sham). Cobalt chloride (CoCl(2); 5 mM) or vehicle was microinjected into the ventrolateral periaqueductal grey (vlPAG) or dorsolateral periaqueductal grey (dlPAG) prior to treatment with TENS. Either high (100 Hz) or low (4 Hz) frequency TENS was then applied to the inflamed knee for 20 min. Active TENS significantly increased withdrawal thresholds of the paw and knee joint in the group microinjected with vehicle when compared to thresholds prior to TENS (P<0.001) or to sham TENS (P<0.001). The increases in withdrawal thresholds normally observed after TENS were prevented by microinjection of CoCl(2) into the vlPAG, but not the dlPAG prior to TENS and were significantly lower than controls treated with TENS (P<0.001). In a separate group of animals, microinjection of CoCl(2) into the vlPAG temporarily reversed the decreased mechanical withdrawal threshold suggesting a role for the vlPAG in the facilitation of joint pain. No significant difference was observed for dlPAG. We hypothesize that the effects of TENS are mediated through the vlPAG that sends projections through the RVM to the spinal cord to produce an opioid-mediated analgesia. 10.1016/j.neuroscience.2009.06.056
Comparison of intra-articular administration of adenosine, lidocaine and magnesium solution and tranexamic acid for alleviating postoperative inflammation and joint fibrosis in an experimental model of knee arthroplasty. Journal of orthopaedic surgery and research BACKGROUND:Dysregulated inflammatory responses are implicated in the pathogenesis of joint stiffness and arthrofibrosis following total knee arthroplasty (TKA). The purpose of this study was to compare the effects of intra-articular (IA) administration of tranexamic acid (TXA), an anti-fibrinolytic commonly used in TKA, and ALM chondroprotective solution on postoperative inflammation and joint tissue healing in a rat model of knee implant surgery. METHODS:Male Sprague-Dawley rats (n = 24) were randomly divided into TXA or ALM treatment groups. The right knee of each rat was implanted with titanium (femur) and polyethylene (tibia) implants. An IA bolus (0.1 ml) of TXA or ALM was administered after implantation and capsule closure, and before skin closure. Postoperative coagulopathy, haematology and systemic inflammatory changes were assessed. Inflammatory and fibrotic markers were assessed in joint tissue, 28 days after surgery. RESULTS:Haemostasis was comparable in animals treated with TXA or ALM after knee implant surgery. In contrast to ALM-treated animals, systemic inflammatory markers remained elevated at day 5 (IL-6, IL-12, IL-10, platelet count) and day 28 (IL-1β, IL-10) following surgery in TXA-treated animals. At day 28 following surgery, the extension range of motion of operated knees was 1.7-fold higher for ALM-treated animals compared to the TXA group. Key inflammatory mediators (NF-κB, IL-12, IL-2), immune cell infiltration (CD68 cells) and markers of fibrosis (α-SMA, TGF-β) were also lower in capsular tissue of ALM-treated knees at day 28. CONCLUSION:Data suggest that IA administration of ALM is superior to TXA for reducing postoperative systemic and joint inflammation and promoting restoration of healthy joint tissue architecture in a rat model of TKA. Further studies are warranted to assess the clinical translational potential of ALM IA solution to improve patient outcomes following arthroplasty. 10.1186/s13018-021-02871-y
IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis. Rath-Wolfson L,Bar-Yehuda S,Madi L,Ochaion A,Cohen S,Zabutti A,Fishman P Clinical and experimental rheumatology OBJECTIVES:The anti-inflammatory effect of adenosine is partially mediated via the A3 adenosine receptor (A3AR), a Gi protein associated cell surface receptor. The highly selective A3AR agonist, IB-MECA was earlier shown to prevent the clinical and pathological manifestations of arthritis in experimental animal models of collagen and adjuvant induced arthritis (AIA). In this study we tested the effect of IB-MECA on the prevention of bone resorption in AIA rats and looked at the molecular mechanism of action. METHODS:Rats with AIA were treated orally twice daily with IB-MECA starting upon onset of disease and the clinical score was evaluated every other day. At study termination the foot, knee and hip region of both vehicle and IB-MECA treated animals were subjected to histomorphometric analysis. Western blot analysis was carried out on paw protein extracts. RESULTS:IB-MECA ameliorated the clinical manifestations of the disease and reduced pannus and fibrosis formation, attenuated cartilage and bone destruction and decreased the number of osteoclasts. In cell protein extracts derived from paw of AIA rats, A3AR was highly expressed in comparison to naïve animals. In paw extracts derived from IB-MECA treated AIA rats, down-regulation of the A3AR protein expression level was noted. PI3K, PKB/Akt, IKK, NF-kappaB, TNF-alpha and RANKL were down-regulated whereas caspase 3 was up-regulated. CONCLUSION:IB-MECA, a small highly bioavailable molecule, induces modulation of proteins which control survival and apoptosis resulting in the amelioration of the inflammatory process and the preservation of bone mass in AIA rats.
Esculetin suppresses proteoglycan metabolism by inhibiting the production of matrix metalloproteinases in rabbit chondrocytes. Watanabe K,Ito A,Sato T,Saito T,Hayashi H,Niitani Y European journal of pharmacology The possible mechanism of the chondroprotective effect of 6,7-dihydroxycoumarin (esculetin) was investigated using primary cultures of rabbit articular chondrocytes. Esculetin (EST) significantly suppressed the proteoglycan depletion and the release of pulse-labeled [35S]proteoglycan from the matrix layer of rabbit chondrocytes treated with recombinant human interleukin-1alpha. The matrix metalloproteinase inhibitor, 1,10-phenanthroline, also blocked the proteoglycan depletion and [35S]proteoglycan release. From these results, it is likely that recombinant human interleukin-1alpha-induced proteoglycan depletion is mediated by matrix metalloproteinases. Although esculetin did not directly inhibit collagenolytic activity in the culture media, it significantly suppressed the production of pro-matrix metalloproteinase-1/interstitial procollagenase and pro-matrix metalloproteinase-3/prostromelysin 1, accompanied by a decrease in the steady-state levels of their mRNAs. These results suggest that esculetin is a therapeutically effective candidate for inhibition of cartilage destruction in osteoarthritis and rheumatoid arthritis. 10.1016/s0014-2999(99)00143-0
Peripheral suppression of arthritic pain by intraarticular fadolmidine, an alpha 2-adrenoceptor agonist, in the rat. Ansah Osei B,Pertovaara Antti Anesthesia and analgesia BACKGROUND:Earlier results suggest that peripheral alpha(2)-adrenoceptors and opioid receptors may reduce arthritic pain. Fadolmidine is a highly selective alpha(2)-adrenoceptor agonist that has only limited central access after peripheral administration. We assessed the peripheral antinociceptive properties of fadolmidine and the potential contribution of peripheral opioid receptors to its antinociceptive effect in experimental monoarthritis. METHODS:After induction of monoarthritis in the knee joints of rats, we determined the frequency of vocalization induced by repetitive movement of the knee joint. Fadolmidine and clonidine were administered intraarticularly ipsi- or contralateral to the inflamed joint. Reversal of the fadolmidine-induced effect was attempted with subcutaneous (s.c.) administration of atipamezole, an alpha(2)-adrenoceptor antagonist, and intraarticular administration of naloxone methiodide, an opioid receptor antagonist that does not penetrate the blood-brain barrier. RESULTS:Fadolmidine produced a dose-dependent attenuation of the vocalization response to movement of the inflamed knee joint, and this effect was significantly stronger after ipsi- than contralateral drug administration. Clonidine also produced a dose-dependent attenuation of the vocalization response, but this effect was not significantly different after ipsi- versus contralateral drug administration. Fadolmidine-induced antinociception was reversed by s.c. administration of atipamezole. Furthermore, intraarticular administration of naloxone methiodide into the inflamed, but not the contralateral, joint reversed the antinociceptive effect of fadolmidine independent of whether fadolmidine was administered into the inflamed or contralateral joint. CONCLUSIONS:In rats, intraarticular administration of fadolmidine provides a marked suppression of pain-related behavior in arthritis, due to a selective action on peripheral alpha(2)-adrenoceptors and opioid receptors. 10.1213/01.ane.0000265850.08385.a6
Spinal cord amino acid release and content in an arthritis model: the effects of pretreatment with non-NMDA, NMDA, and NK1 receptor antagonists. Sluka K A,Westlund K N Brain research An experimental arthritis, induced by injection of the knee joint with kaolin and carrageenan, results in guarding of and decreased weight bearing on the limb. At the time of injection, a transient increased release of all amino acids examined is measurable in samples collected by microdialysis. A second and prolonged increase of aspartate (ASP), glutamate (GLU), and glutamine (GLN) concentrations follows after 3 h. The increased release at time of injection is blocked by microdialysis application of a non-N-methyl-D-aspartate (non-NMDA) or an NMDA receptor antagonist, and the release of ASP, GLU, and GLN in the late phase is blocked by pretreatment with a non-NMDA (CNQX), an NMDA (AP7) or a neurokinin 1 (NK1; CP-96,345) antagonist. Dorsal horn immunoreactive staining of GLU, substance P (SP), and calcitonin gene-related peptide (CGRP) is reflective of the events occurring in the late phase of amino acid release since GLU release is positively correlated with GLU staining density. Increased immunoreactivity for GLU, SP, and CGRP at 8 hr in the arthritic animals is differentially altered by pretreatment of the spinal cord dorsal horn with non-NMDA, NMDA, or NK1 receptor antagonists. The differential staining pattern for GLU, SP, and CGRP, the differential release of ASP and GLU, and the differential activation of the EAA and NK1 receptors implies that ASP, GLU, SP, and CGRP are each involved in the processing of sensory information and that their roles in the central sensitization occurring with the inflammatory process, are unique. 10.1016/0006-8993(93)90752-9
Group I metabotropic glutamate receptor antagonists block secondary thermal hyperalgesia in rats with knee joint inflammation. Zhang Liping,Lu Ying,Chen Ying,Westlund Karin N The Journal of pharmacology and experimental therapeutics Activation of ionotropic glutamate receptors has been shown previously to be essential for the development of secondary thermal hyperalgesia. The present study assessed involvement of group I metabotropic glutamate receptors (mGlu) in both the induction and maintenance phases of secondary thermal hyperalgesia initiated by knee joint inflammation in rats. The dose dependence of each drug in antagonism of thermal hypersensitivity was demonstrated in pre- and post-treatment paradigms. Knee joint inflammation was induced by injection of kaolin and carrageenan. Four hours later the paw withdrawal latencies were significantly shorter than baseline values. Rats were pretreated by spinal microdialysis infusion of group I mGlu receptor antagonists, LY393053 [(+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid], LY367385 [(S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid], or AIDA [(R,S)-1-aminoindan-1,5-dicarboxylic acid/UPF 523] before knee joint injection. The paw withdrawal latencies measured 4 h after the injection were significantly longer in the presence of group I mGlu receptor antagonists than those of the artificial cerebrospinal fluid-treated arthritic control group. Post-treatment with the group I mGlu receptor antagonists LY367385 and AIDA allowed significant recovery of the paw withdrawal latencies after the onset of the knee joint inflammation. The knee joint inflammation itself was not affected by either treatment. The results of the present study indicate that secondary thermal hyperalgesia can be effectively attenuated during both the development and maintenance phases of acute knee joint inflammation by spinal application of specific group I mGlu receptor antagonists. 10.1124/jpet.300.1.149
Inhibition of rats adjuvant arthritis by a bradykinin antagonist Hoe 140 and its influence on kallikreins. Sharma J N,Wirth K J General pharmacology 1. This study examines the effect of Hoe 140, a bradykinin (BK) 2 receptor antagonist, indomethacin and prednisolone on chronic adjuvant arthritis of the knee in rats. We also evaluated the influence of Hoe 140 on BK-forming enzymes in the synovial and paw tissues. 2. Adjuvant arthritis was induced in male Sprague-Dawley rats in the right knee by injecting 0.05 ml of a fine suspension of heat-killed Mycobacterium tubercle bacilli in liquid paraffin (5 mg/ml). 3. Hoe 140 (1.5 mg/kg i.p.), indomethacin (2.5 mg/kg orally) and prednisolone (3.0 mg/kg orally) administration for 9 days resulted in significant suppression of knee joint swelling. Plasma and tissue kallikrein levels were raised (P < 0.01) in the synovial and paw tissues of adjuvant arthritic rats. Hoe 140 treatment reduced (P < 0.05) tissue kallikrein but increased (P < 0.01) plasma kallikrein levels in synovial tissue. 4. Hoe 140 treatment did not alter (P > 0.05) the raised plasma and tissue kallikrein levels in the paw tissue. The findings indicate that Hoe 140 may be a useful anti-inflammatory agent and BK plays a major role in this adjuvant-induced arthritis model.
Nociception contributes to the formation of myogenic contracture in the early phase of adjuvant-induced arthritis in a rat knee. Kaneguchi Akinori,Ozawa Junya,Moriyama Hideki,Yamaoka Kaoru Journal of orthopaedic research : official publication of the Orthopaedic Research Society It is unknown how joint contracture is generated in inflamed joints. This study aimed to clarify the role of nociception on the formation of joint contracture secondary to arthritis. Monoarthritis was induced by intra-articular injections of complete Freund's adjuvant (CFA) into rat knees. On day 5 after CFA injection, the passive extension range of motion (ROM) of knee joints were measured, both before and after myotomy of knee flexors, to evaluate the extent of muscular contribution to CFA-induced joint contracture. The steroidal anti-inflammatory drug dexamethasone could prevent ROM restrictions completely, both before and after myotomy. On the other hand, the opioid analgesic drug morphine did not prevent the development of restricted ROM observed after myotomy, while it did before myotomy. This indicates that nociception contributes to joint contracture through alterations in muscular structure (myogenic factors). Next, we tested the hypothesis that nociception-induced reflexive flexor muscle contractions cause myogenic contracture in arthritic joints. To do this, chemical denervation was performed by Botulinum toxin type A (BTX-A) injections into knee flexor muscles, simultaneously with CFA injections into the knee. As expected, BTX-A could alleviate ROM restrictions observed before myotomy. These findings suggest that nociceptive-related muscle contractions play an essential role in the formation of joint contracture. Thus, our study indicates that analgesic management during an early stage of joint arthritis is an essential mean to prevent the formation of joint contracture. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1404-1413, 2017. 10.1002/jor.23412
Modulation of IL-1 effects on cartilage by NO synthase inhibitors: pharmacological studies in rats. Jouzeau J Y,Cipolletta C,Presle N,Netter P,Terlain B Osteoarthritis and cartilage Objective To compare the ability of L-arginine (L-arg) analog nitric oxide synthase (NOS) inhibitors and isothioureas to restore the interleukin-1 (IL-1) induced inhibition of proteoglycan (PG) synthesis in rat.Methods Chondrocytes beads and patellae were challenged with IL-1betain vitro and monitored for NO production and proteoglycan synthesis. Rats injected with IL-1beta in knee joints were monitored for NO(2)( - )+NO(3)( - )levels in joint tissues and ex-vivo(35)S sulfate incorporation in patellae. NOS inhibitors were either added to culture medium or injected concomittantly to IL-1beta. Results Ability of NOS inhibitors to reduce NO(2)( - )levels decreased from chondrocytes beads to patellae. Partial restoration of PG synthesis was restricted to L-arg analogs in patellae. After IL-1 injection, NO was produced from patella and synovium. L-arg analogs restored partly PG synthesis when decreasing significantly NO(2)( - )+NO(3)( - )levels in synovial fluid. Isothioureas were ineffective. Conclusions NO accounts importantly for IL-1 induced inhibition of cartilage anabolism in rat. L-arg analog NOS inhibitors are more effective than isothioureas in restoring PG synthesis and have chondroprotective potency when administered locally in diseased joint. 10.1053/joca.1998.0218
Abrogation of alpha-adrenergic vasoactivity in chronically inflamed rat knee joints. McDougall J J American journal of physiology. Regulatory, integrative and comparative physiology It has previously been shown that chronic inflammation causes a reduction in sympathetic nerve-mediated vasoconstriction in rat knees. To determine whether this phenomenon is due to an alteration in smooth muscle adrenoceptor function, the present study compared the alpha-adrenoceptor profile of blood vessels supplying the anteromedial capsule of normal and chronically inflamed rat knee joints. While the rats were under urethan anesthesia, the alpha(1)-adrenoceptor agonists methoxamine and phenylephrine and the alpha(2)-adrenoceptor agonist clonidine (0.1-ml bolus; dose range 10(-12)-10(-7) mol) were applied to exposed normal rat knees, resulting in a dose-dependent fall in capsular perfusion. Comparison of drug potencies indicated that alpha(2)-adrenergic effects > alpha(1)-vasoactivity. One week after intra-articular injection of Freund's complete adjuvant to induce chronic joint inflammation, the vasoconstrictor effects of methoxamine, phenylephrine, and clonidine were all significantly attenuated compared with normal controls. These findings show that the preponderance of sympathetic adrenergic vasoconstriction in the anteromedial capsule of the rat is carried out by postjunctional alpha(2)-adrenoceptors. Chronic joint inflammation compromises alpha(1)- and alpha(2)-adrenoceptor function, and this change in alpha-adrenergic responsiveness may help explain the perfusion changes commonly associated with inflammatory arthritis. 10.1152/ajpregu.2001.281.3.R821
Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats. Desantana Josimari M,Santana-Filho Valter J,Sluka Kathleen A Archives of physical medicine and rehabilitation OBJECTIVE:To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance. DESIGN:Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%-2%). SETTING:Laboratory. ANIMALS:Adult male Sprague-Dawley rats (N=36). INTERVENTION:Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100micros pulse duration. MAIN OUTCOME MEASURES:Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS. RESULTS:The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds. CONCLUSIONS:These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop. 10.1016/j.apmr.2007.11.027
Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2-deficient mice and in anti-interleukin-1-treated wild-type mice with unabated joint inflammation. van de Loo F A,Arntz O J,van Enckevort F H,van Lent P L,van den Berg W B Arthritis and rheumatism OBJECTIVE:To investigate the role of nitric oxide (NO) and interleukin-1 in (IL-1) joint inflammation and cartilage destruction during zymosan-induced gonarthritis (ZIA). METHODS:Monarticular arthritis was elicited by intraarticular injection of zymosan. The effect of NO deficiency on arthritis was studied in mice with genetically disrupted NOS2. The role of IL-1 was examined by treating wild-type mice with neutralizing anti-murine IL-1(alpha+beta) antibodies. Joint swelling was measured externally by the increased uptake of circulating 99mtechnetium pertechnetate. Proteoglycan (PG) synthesis was assessed using 35S-sulfate incorporation into patellae ex vivo. Histology evaluated exudation and infiltration of leukocytes and the extent of cartilage destruction. RESULTS:The proinflammatory mediators NO, IL-1, and IL-6 were released by the articular tissues during the first hours of inflammation. Interestingly, anti-IL-1 treatment moderately reduced, and NOS2 deficiency moderately enhanced, joint swelling. However, the influx of neutrophils into the joint occurred independently of IL-1 and NOS2 activities. In the first week of inflammation, chondrocyte PG synthesis was significantly suppressed and chondrocytes became unresponsive to their essential anabolic factor, insulin-like growth factor 1 (IGF-1). Anti-IL-1 treatment or NOS2 deficiency prevented the inhibition of PG synthesis, and the chondrocytes remained IGF-1 responsive. Intraarticular injections of IL-1alpha into NOS2-deficient mice did not affect PG synthesis, thus proving that NO mediated this IL-1 effect in vivo. Furthermore, histology showed that cartilage PG loss was markedly ameliorated in NOS2-deficient and anti-IL-1-treated mice. Intermediate cartilage pathology was found in mice that were heterozygous for disrupted NOS2. CONCLUSION:IL-1 and NO play a minor role in edema and neutrophil influx, but a major role in cartilage destruction of ZIA. In this model of murine arthritis, cartilage destruction was, for the most part, caused by pronounced suppression of PG synthesis and IGF-1 unresponsiveness of the chondrocytes, which were induced by de novo-synthesized IL-1 and were mediated by NOS2 activation. 10.1002/1529-0131(199804)41:4<634::AID-ART10>3.0.CO;2-1
Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis. Bassi Gabriel S,do C Malvar David,Cunha Thiago M,Cunha Fernando Q,Kanashiro Alexandre Naunyn-Schmiedeberg's archives of pharmacology Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK. 10.1007/s00210-016-1248-0
Spinal 5-HT receptor is involved in electroacupuncture inhibition of chronic pain. Molecular pain Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, and it is a typical disease which can develop chronic pain. Our previous study has proved that endocannabinoid (2-AG)-CB1R-GABA-5-HT pathway is involved in electroacupuncture (EA) mediated inhibition of chronic pain. However, it is still unclear which among the 5-HT receptor subtype is involved in EA evoked 5-HT mediated inhibition of chronic pain in the dorsal spinal cord. 5-HT is a G protein-coupled receptor and it is involved in 5-HT descending pain modulation system. We found that EA treatment at frequency of 2 Hz +1 mA significantly increased the expression of 5-HT receptor in the dorsal spinal cord and intrathecal injection of 5-HT receptor antagonist or agonist reversed or mimicked the analgesic effect of EA in each case respectively. Intrathecal injection of a selective GABA receptor antagonist Bicuculline also reversed the EA effect on pain hypersensitivity. Additionally, EA treatment reversed the reduced expression of GABA receptor and KCC2 in the dorsal spinal cord of KOA mice. Furthermore, we demonstrated that intrathecal 5-HT receptor antagonist/agonist reversed or mimicked the effect of EA up-regulate of KCC2 expression, respectively. Similarly, intrathecal injection of PLC and PKC inhibitors prevented both anti-allodynic effect and up-regulation of KCC2 expression by EA treatment. Our data suggest that EA treatment up-regulated KCC2 expression through activating 5-HT-Gq-PLC-PKC pathway and enhanced the inhibitory function of GABA receptor, thereby inhibiting chronic pain in a mouse model of KOA. 10.1177/17448069221087583
Effect of NGF antibodies on mast cell distribution, histamine and substance P levels in the knee joint of TNF-arthritic transgenic mice. Aloe L,Probert L,Kollias G,Micera A,Tirassa P Rheumatology international We have previously shown an increase in nerve growth factor (NGF) levels and in mast cell (MC) distribution in the synovium of patients affected by rheumatoid arthritis. We now report that purified NGF antibodies injected into arthritic transgenic mice carrying the human tumour necrosis factor-alpha (TNF-alpha) gene caused reduction in the number of MCs, as well as a decrease in histamine and substance P levels within the synovium. These observations suggest that NGF antibody might be useful in studying the role of these pro-inflammatory markers in joint arthritis. 10.1007/bf00262091
Intraarticular pretreatment with ketamine and memantine could prevent arthritic pain: relevance to the decrease of spinal c-fos expression in rats. Zhang Guo Hua,Min Sun Seek,Lee Kyu Sang,Back Seung Keun,Yoon Seong Jun,Yoon Young Wook,Kim Yang In,Na Heung Sik,Hong Seung Kil,Han Hee Chul Anesthesia and analgesia To determine whether intraarticular pretreatment with N-methyl-D-aspartic (NMDA) receptor antagonist ketamine or memantine currently used in humans has prophylactic analgesia in arthritic pain, we examined the effects of their intraarticular injection before carrageenan injection into the knee joint on pain-related behavior and spinal c-Fos expression in rats. Injection of ketamine (0.2 mg and 1 mg) or memantine (0.1 mg, 0.2 mg, and 1 mg) into the knee joint, but not the abdominal cavity, immediately before carrageenan injection (2%, 40 microL) significantly prevented pain-related behavior. The intraarticular injection of ketamine (1 mg) or memantine (0.2 mg) also suppressed c-Fos expression in the laminae I-II and laminae V-VI at the L3-4 spinal level. Subsequent statistical analyses revealed that the degree of the spinal c-Fos expression was correlated with the extent of the pain-related behavior. These results suggest that peripheral administration of NMDA receptor antagonists has prophylactic analgesic effects in arthritic pain, which might be associated with the decrease of central nociceptive signaling. Because ketamine and memantine are currently used in humans and considered clinically safe, they may have therapeutic value in the treatment of joint pain. 10.1213/01.ANE.0000117141.76392.65
5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. Molecular pain BACKGROUND:Pain, including arthritic pain, has a negative affective component and is often associated with anxiety and depression. However, selective serotonin reuptake inhibitor antidepressants (SSRIs) show limited effectiveness in pain. The amygdala plays a key role in the emotional-affective component of pain, pain modulation and affective disorders. Neuroplasticity in the basolateral and central amygdala (BLA and CeA, respectively) correlate positively with pain behaviors. Evidence suggests that serotonin receptor subtype 5-HT2CR in the amygdala contributes critically to anxiogenic behavior and anxiety disorders. In this study, we tested the hypothesis that 5-HT2CR in the amygdala accounts for the limited effectiveness of SSRIs in reducing pain behaviors and that 5-HT2CR blockade in the amygdala renders SSRIs effective. RESULTS:Nocifensive reflexes, vocalizations and anxiety-like behavior were measured in adult male Sprague-Dawley rats. Behavioral experiments were done in sham controls and in rats with arthritis induced by kaolin/carrageenan injections into one knee joint. Rats received a systemic (i.p.) administration of an SSRI (fluvoxamine, 30 mg/kg) or vehicle (sterile saline) and stereotaxic application of a selective 5-HT2CR antagonist (SB242084, 10 μM) or vehicle (ACSF) into BLA or CeA by microdialysis. Compared to shams, arthritic rats showed decreased hindlimb withdrawal thresholds (increased reflexes), increased duration of audible and ultrasonic vocalizations, and decreased open-arm choices in the elevated plus maze test suggesting anxiety-like behavior. Fluvoxamine (i.p.) or SB242084 (intra-BLA) alone had no significant effect, but their combination inhibited the pain-related increase of vocalizations and anxiety-like behavior without affecting spinal reflexes. SB242084 applied into the CeA in combination with systemic fluvoxamine had no effect on vocalizations and spinal reflexes. CONCLUSIONS:The data suggest that 5-HT2CR in the amygdala, especially in the BLA, limits the effectiveness of SSRIs to inhibit pain-related emotional-affective behaviors. 10.1186/1744-8069-9-41
The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line. Mistry D,Chambers M G,Mason R M Osteoarthritis and cartilage OBJECTIVE:To investigate the role of adenosine in chondrocyte death in murine osteoarthritis (OA). METHODS:5'-Nucleotidase (5'NT) generates adenosine. Enzyme activity was measured histochemically in normal murine and osteoarthritic STR/ort strain tibial cartilage. Adenosine-mediated cell death was investigated in MC615 chondrocyte cultures. Adenosine receptors (ARs) were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). Cellular uptake of [(3)H] adenosine was measured with or without the inhibitor, nitrobenzylthioinosine (NBTI). Cell death was assessed by cell counting and DNA laddering following selective receptor stimulation, or after modulating adenosine metabolism with adenosine deaminase (ADA) or adenosine kinase (AK) inhibitors [erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and Iodotubericidin (Itub)], or with homocysteine (HC). Markers of apoptosis were assessed by Western blotting. Cell studies were validated by incubating normal murine knee joints in a medium containing adenosine and metabolic inhibitors. Apoptotic chondrocytes were identified with the TUNEL reaction. RESULTS:5'NT activity in STR/ort tibial cartilage increased with development of OA, especially close to OA lesions. Adenosine induced MC615 cell death in the presence of ADA inhibition (100 microM EHNA), or 1mM HC, or both. Adenosine uptake, mediated by NBTI-sensitive adenosine transporters, was required for cell death. ARs were expressed (A2b>A2a>A1) but were not involved in mediating cell death. Cell death involved the activation of caspase-3 and DNA fragmentation and was prevented by inhibiting caspase activity. However, neither caspase-8 nor caspase-9 was detected. Adenosine+EHNA induced chondrocyte apoptosis in normal murine knee joints. CONCLUSION:Increased adenosine production may induce chondrocyte apoptosis and play a role in OA in STR/ort mice. 10.1016/j.joca.2005.11.015
Mechanical stress and prostaglandin E2 synthesis in cartilage. Gosset Marjolaine,Berenbaum Francis,Levy Arlette,Pigenet Audrey,Thirion Sylvie,Cavadias Simeon,Jacques Claire Biorheology Knee osteoarthritis (OA) results, at least in part, from overloading and inflammation leading to cartilage degradation. Prostaglandin E2 (PGE2) is one of the main catabolic factors involved in OA in which metalloproteinase (MMP) is crucial for cartilage degradation. Its synthesis is the result of cyclooxygenase (COX) and prostaglandin E synthase (PGES) activities whereas NAD+-dependent 15 hydroxy-prostaglandin dehydrogenase (15-PGDH) is the key enzyme implicated in the catabolism of PGE2. Among the isoforms described, COX-1 and cytosolic PGES are constitutively expressed whereas COX-2 and microsomal PGES type 1 (mPGES-1) are inducible in an inflammatory context. We investigated the regulation of the COX, PGES and 15-PGDH and MMP-2, MMP-9 and MMP-13 genes by mechanical stress applied to cartilage explants. Mouse cartilage explants were subjected to compression (0.5 Hz, 1 MPa) from 2 to 24 h. After determination of the PGE2 release in the media, mRNA and proteins were extracted directly from the cartilage explants and analyzed by real-time RT-PCR and western blot respectively. Mechanical compression of cartilage explants significantly increased PGE2 production in a time dependent manner. This was not due to the synthesis of IL-1, since pretreatment with IL1-Ra did not alter the PGE2 synthesis. Interestingly, COX-2 and mPGES-1 mRNA expression significantly increased after 2 hours, in parallel with protein expression. Moreover, we observed a delayed overexpression of 15-PGDH just before the decline of PGE2 synthesis after 18 hours suggesting that PGE2 synthesis could be altered by the induction of 15-PGDH expression. MAPK are involved in signaling, since specific inhibitors partially inhibited COX-2 and mPGES-1 expressions. Lastly, compression induced MMP-2, -9, -13 mRNA expressions in cartilage. We conclude that dynamic compression induces pro-inflammatroy mediators release and matrix degradating enzymes synthesis. Notably, compression increases mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis.
Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function. Bassi Gabriel S,Brognara Fernanda,Castania Jaci A,Talbot Jhimmy,Cunha Thiago M,Cunha Fernando Q,Ulloa Luis,Kanashiro Alexandre,Dias Daniel P Martins,Salgado Helio C Brain, behavior, and immunity The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation. 10.1016/j.bbi.2015.05.002
Intraspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo--a study with antibody microprobes in cat and rat. Schaible H G,Freudenberger U,Neugebauer V,Stiller R U Neuroscience This study addressed the intraspinal release of immunoreactive calcitonin gene-related peptide in vivo during mechanical stimulation of the normal joint and during the development of an acute experimental inflammation in the knee joint in the anaesthetized cat (spinalized) and rat (not spinalized). Release was assessed using microprobes coated with antibody to calcitonin gene-related peptide; inhibition of binding of [125I]calcitonin gene-related peptide to these probes following insertion into the spinal cord is equated with intraspinal release of the endogenous (unlabelled) peptide. Probes inserted prior to inflammation showed marked basal release of immunoreactive calcitonin gene-related peptide in the dorsal horn with a maximum in the superficial dorsal horn in the absence of intentional stimulation. The pattern of binding of [125I]calcitonin gene-related peptide was not or only minimally changed by innocuous mechanical stimuli (flexion of and innocuous pressure to the knee in the cat and innocuous pressure to the knee of the rat) but was significantly altered by electrical stimulation of the tibial nerve in the cat (sufficient to excite unmyelinated afferent fibres), indicating release of the peptide by the latter stimulus. During the first hours of the development of an experimental inflammation in the knee joint induced by intra-articular injections of kaolin and carrageenan, the pattern of binding of [125I]calcitonin gene-related peptide changed. In the cat, the level of immunoreactive calcitonin gene-related peptide showed a persistent increase in the gray matter and up to the surface of the cord and release was slightly increased by innocuous stimuli. In the rat, increased levels of immunoreactive calcitonin gene-related peptide were mainly seen in the superficial and deep dorsal horn during innocuous pressure (this stimulus did not evoke release of the peptide prior to inflammation) and noxious pressure applied to the injected knee, whereas increased basal levels were only observed at later stages. These data show that the development of an acute experimental inflammation in the joint is associated with an enhancement of the intraspinal release of immunoreactive calcitonin gene-related peptide. Since the changes in the release were noted at an early stage, within the first hours, they could contribute to the generation of inflammation-evoked changes of the responsiveness of spinal cord neurons and hence to the mechanisms inducing inflammatory pain. 10.1016/0306-4522(94)90361-1
Adenosine A1 receptor-mediated excitation of nociceptive afferents innervating the normal and arthritic rat knee joint. Dowd E,McQueen D S,Chessell I P,Humphrey P P British journal of pharmacology We tested the hypothesis that adenosine excites nociceptive primary afferents innervating the knee joint. Neuronal recordings were made from fine nerve filaments innervating the knee joint in rats anaesthetized with pentobarbitone. Drugs were injected close-arterially (i.a.) or into the articular space (i.art.). We studied normal and chronically inflamed arthritic joints, the latter 14-21 days after a single intra-articular injection of Freund's Complete Adjuvant, performed under halothane anaesthesia. Adenosine injected i.a. caused delayed (approximately 10 s) excitation of the majority of polymodal C-fibre afferents, and had similar effects when injected directly into the joint. Adenosine triphosphate (ATP) had biphasic effects on discharge, a fast (<1 s) excitation was followed by a delayed increase similar to that seen with adenosine. The adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and N-[(1S,trans)-2-hydroxypentyl] adenosine (GR79236) also excited the C-fibre afferents. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) antagonized the responses evoked by adenosine, CPA, and the delayed increase seen after ATP, indicating that excitation of the nociceptive afferents was mediated via adenosine A1 receptors. Adenosine and ATP evoked delayed excitatory effects of similar magnitude, regardless of whether or not the knee joint was chronically inflamed. The increased basal discharge observed in arthritic joints was unaffected by DPCPX, which implies that the increase in spontaneous activity associated with arthritis is unlikely to involve tonically released adenosine. The results support the hypothesis that adenosine excites primary afferent nociceptive nerve terminals in the rat knee joint, an effect mediated by adenosine A1 receptors. ATP, adenosine, and A1 receptors may play a role in generating the peripheral nociceptive (pain) signal. 10.1038/sj.bjp.0702185
Responses of blood vessels in the rabbit knee to acute joint inflammation. Annals of the rheumatic diseases These experiments examined the responses of articular blood vessels in the rabbit knee to induction of acute joint inflammation by intraarticular injection of 4% kaolin suspension. This produced an inflammatory response, which became evident about four hours after injection. Electrical stimulation of the nerve supply to the knee joint before induction of inflammation produced a biphasic response--an initial vasoconstriction during the stimulation phase followed by dilatation after stimulation stopped. These responses were followed up for eight hours and it was noted that the constrictor response became progressively greater, producing a further 19% decrease in blood flow during nerve stimulation about three hours after the injection of kaolin. The sensitivity of postjunctional alpha adrenoceptors, however, showed still greater increase in the inflamed joint as close intraarterial injection of 10(-6) M adrenaline produced an additional 30% reduction in blood flow four hours after kaolin injection compared with the control response. Possibly, the smaller enhancement of the constrictor response to nerve stimulation in the inflamed joint may reflect sensitisation of prejunctional alpha adrenoceptors in addition to the effects exerted on postjunctional alpha adrenoceptors by the inflammatory process. The dilator response also increased over eight hours, though this rise was less marked. These findings indicate that even over the limited time span of the experiments, significant alterations occurred in factors which influence the calibre of articular blood vessels. 10.1136/ard.49.7.540
Acute inflammation of the knee joint in the cat alters responses of flexor motoneurons to leg movements. He X,Proske U,Schaible H G,Schmidt R F Journal of neurophysiology 1. This is a report of changes in reflex excitability of flexor motoneurons in response to innocuous mechanical stimuli following initiation of an acute experimental inflammation of the knee joint in the chloralose-anaesthetized cat spinalized at level T12. 2. Activity of functionally single alpha- or gamma- motoneurons, identified by ventral root stimulation, was recorded in filaments of the nerve to biceps semitendinosus before and after onset of an acute inflammation. The inflammation was evoked by injection into the knee cavity of the compounds kaolin and carrageenan. 3. Measurements were made of resting activity, responses to local pressure applied to parts of the upper or lower limb, and to flexion or extension movements at the knee joint before and after onset of the inflammation. In two experiments, one in which no inflammation was initiated, and another in which recordings were made only after the inflammation had fully developed, a survey of large numbers of neurons (44 alpha and 84 gamma) showed that under control conditions only 14% of alpha-motoneurons showed a response to mechanical stimulation compared with 41% of gamma-motoneurons. In the presence of an inflammation 41% of alpha-cells were responsive compared with 64% of gamma-cells. 4. Inflammation-induced changes in activity of motoneurons including both excitatory and inhibitory effects, took 1-2 h to fully develop. Excitatory effects included a rise in resting discharge, an increase in the response to local pressure, and an increased response to flexion and/or to extension of the knee. Inhibitory effects included falls in resting discharge and/or in the responses to leg movements. 5. For 35 cells identified as alpha-motoneurons and tested both before and after initiation of an inflammation, 20 remained unresponsive throughout the experiment, whereas 4 that had not responded during the control period began after inflammation to respond to local pressure and/or flexion/extension movements. Of 11 units that exhibited some response before inflammation, 8 showed an increase with inflammation, whereas 2 became unresponsive. 6. The inflammation had rather more dramatic effects on gamma-neurons. Many showed control responses to leg movements, and these were measurably modified by inflammation. Of 56 gamma-cells tested under control conditions, 26 were unresponsive to all stimuli, whereas 30 showed some form of response including activity during flexion and extension movements of the leg. Where responses were tested both before and after onset of an inflammation, 11 of 13 unresponsive units remained unresponsive.(ABSTRACT TRUNCATED AT 400 WORDS) 10.1152/jn.1988.59.2.326
Leukocyte trafficking and pain behavioral responses to a hydrogen sulfide donor in acute monoarthritis. Andruski Benjamin,McCafferty Donna-Marie,Ignacy Teegan,Millen Brandie,McDougall Jason J American journal of physiology. Regulatory, integrative and comparative physiology Hydrogen sulfide (H(2)S) is an endogenous gaseous mediator with the ability to modulate tissue inflammation and pain. The aim of this study was to determine the effect of an H(2)S donor (Na(2)S) on leukocyte-endothelium interactions, blood flow, and pain sensation in acutely inflamed knee joints. Acute arthritis was induced in urethane anesthetized C57bl/6 mice by intra-articular injection of kaolin/carrageenan (24-h recovery), and the effect of local administration of Na(2)S on leukocyte trafficking was measured by intravital microscopy. Synovial blood flow was measured in inflamed knees by laser Doppler perfusion imaging. Finally, the effect of an intra-articular injection of Na(2)S on joint pain in control and inflamed rats was determined by hindlimb incapacitance and von Frey hair algesiometry. Local administration of an H(2)S donor to inflamed knees caused a dose-dependent reduction in leukocyte adherence and an increase in leukocyte velocity. These effects could be inhibited by coadministration of the ATP-sensitive K(+) channel blocker glibenclamide. Local administration of Na(2)S to inflamed joints caused a pronounced vasoconstrictor response; however, there was no observable effect of Na(2)S on joint pain. These findings establish H(2)S as a novel signaling molecule in rodent knee joints. H(2)S exhibits potent anti-inflammatory properties, but with no detectable effect on joint pain. 10.1152/ajpregu.90524.2008
Regulation of murine arthritis by systemic, spinal, and intra-articular adrenoceptors. Pharmacological reports : PR BACKGROUND:The regulation of the immune system by the sympathetic nervous system is allowing the design of novel treatments for inflammatory disorders such as arthritis. In this study, we have analyzed the effects of α- and β-adrenoceptor agonists injected subcutaneously, intrathecally, or intra-articularly in zymosan-induced arthritis. METHODS:Murine arthritis was induced by intra-articular (knee joint) injection of zymosan. α1 (phenylephrine), α2 (clonidine), β1 (dobutamine), or β2 (salbutamol)-adrenoceptor agonists were injected subcutaneously (sc), intrathecally (it), or intra-articularly (ia) to activate peripheral, spinal, or intra-articular adrenoceptors and to study their effects on articular edema formation and neutrophil migration into the synovial cavity. RESULTS:Treatments with phenylephrine did not affect the edema formation, but it increased neutrophil migration when injected subcutaneously (155.3%) or intra-articularly (187.7%). Treatments with clonidine inhibited neutrophil migration (59.9% sc, 68.7% it, 42.8% ia) regardless of the route of administration, but it inhibited edema formation only when injected intrathecally (66.7%) or intra-articularly (36%) but not subcutaneously. Treatments with dobutamine inhibited both edema (42.0% sc, 69.5% it, 61.6% ia) and neutrophil migration (28.4% sc, 70.3% it, 82.4% ia) in a concentration dependent manner. Likewise, all the treatments with salbutamol also inhibited edema formation (89.9% sc, 62.4% it, 69.8% ia) and neutrophil migration (76.6% sc, 39.1% it, 71.7% ia). CONCLUSION:Whereas the β-adrenoceptor agonists induced anti-inflammatory effects regardless of their route of administration, α1- and α2-adrenoceptor agonists induced either pro- and anti-inflammatory effects, respectively. 10.1016/j.pharep.2019.06.010
Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats. Lu Y,Westlund K N The Journal of pharmacology and experimental therapeutics In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. Both pretreatment and post-treatment protocols were examined. Spinal administration of gabapentin (10 mg/ml) infused 1.5 h before induction of knee joint inflammation, although having no effect on the baseline, prevented the development of heat hyperalgesia. Gabapentin also prevented the development of other pain-related behaviors scored subjectively. Gabapentin had no effect, however, on the joint circumference increase typical in this model. In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism.
Nicotinic cholinergic receptors: potential targets for inflammatory pain relief. Lawand N B,Lu Y,Westlund K N Pain We have shown previously that the development of hyperalgesia and inflammation associated with knee joint arthritis depends on interactions among various receptors in the central and peripheral nervous system in addition to the contribution of blood borne inflammatory mediators. In the present study, the involvement of spinal nicotinic cholinergic receptors in the modulation of inflammatory pain was evaluated using a model of acute arthritis in rats. Epibatidine (EP), a potent agonist for neuronal nicotinic acetylcholine receptors sharing similar structural and functional characteristics with acetylcholine and nicotine, has been used in this study. The physiological effects of EP on pain-related behaviors and inflammation were tested after administration to the dorsal horn via a microdialysis fiber. Knee joint inflammation was induced in rats by injecting a mixture of kaolin and carrageenan into the knee joint. Paw withdrawal latency to radiant heat was measured before and at 4, 5, 6, 7 and 8 h after induction of inflammation. The decrease in PWL in this arthritis model is indicative of secondary hyperalgesia. The extent of peripheral inflammation was also assessed by measuring knee joint circumference and temperature. Treatment of the spinal cord of animals with EP prior to induction of arthritis attenuated the development of heat hyperalgesia and resulted in a significant improvement of the animals' spontaneous pain-related behaviors. More interestingly, the knee joint circumference and temperature of these animals were also significantly lower than those of the control animals when measured at 8 h. Likewise, spinal administration of epibatidine after the development of hyperalgesia not only significantly attenuated the decrease in PWL, but prevented further increases in knee joint swelling and temperature. The antinociceptive effect of epibatidine was selectively blocked by the nicotinic receptor antagonist, mecamylamine. Joint circumference and temperature were not selectively altered by mecamylamine suggesting another mechanism involving non-nicotinic receptors in the spinal regulation of joint inflammatory responses. Collectively, these findings provide considerable evidence to suggest an important role for central nicotinic cholinergic receptors in the modulation of persistent pain and neurogenic inflammation mediated by events in the dorsal horn. 10.1016/s0304-3959(98)00221-8
[Effect of extracorporeal shock wave therapy on cartilage and subchondral bone remodeling in rabbits with ACLT-induced osteoarthritis]. Wang Pu,Liu Chuan,Yang Xiao-Tian,Wei Xiao-Fei,Zhou Yu-Jing,Yang Lin,He Cheng-Qi Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition OBJECTIVE:To investigate the role of extracorporeal shock wave therapy on the protection of cartilage and subchondral bone remodeling in rabbits with osteoarthritis induced by anterior cruciate ligament transaction (ACLT). METHODS:Anterior cruciate ligament transaction was performed on 24 adult rabbits to establish knee osteoarthritis models. The rabbits were randomly divided into two groups, with one group receiving extracorporeal shock wave therapy (ESWT) and the other group serving as controls. The ESWT was set at energy 0.16 MPa/time, frequency 5 Hz, 1 200 shock per side, 3 times per week, and a total of 6 times in 4 weeks. Histological observations were undertaken with articular cartilages under mascroscope and microscope; bone mineral density (BMD) was measured. The subchondral bones of femoralcondyle and tibial plateau were given a bone histomorphometry analysis. The levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) were detected by ELISA. The expressions of matrix metalloproteinases (MMP-1, MMP 3, MMP-13) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in cartilage were determined by RT-PCR. RESULTS:Lower levels of histological result in medial femoral condyles (by both mascroscope and microscope examinations) and higher levels of BMD (in distal femora) were found in the ESWT treated rabbits compared with the controls (P < 0.05). The ESWT treated rabbits also had decreased trabecular bone relative volume and trabecular bone thickness, increased bone separation, lower levels of expressions of MMP-1 and MMP-3, and higher levels of TIMP-1. CONCLUSION:ESWT can protect cartilage from damages and prevent subchondral sclerosis through regulating MMP-1, MMP-3 and TIMP-1 in cartilages and modulating subchondral bone metabolisms.
Chronic secondary hypersensitivity of dorsal horn neurones following inflammation of the knee joint. Martindale J C,Wilson A W,Reeve A J,Chessell I P,Headley P M Pain Intra-articular injection of Freund's complete adjuvant (FCA) into the rat knee joint produces a swelling of the joint and long lasting hypersensitivity. In this study we have used this model and in vivo electrophysiology to investigate the time course of spinal changes underlying chronic secondary hypersensitivity, by stimulating the ankle joint (an area outside the site of primary hypersensitivity), and have compared the results with behavioural data from the same population of animals at 4-8, 13-17 and 55-59 days following FCA injection. The magnitude of responses and the proportion of dorsal horn neurones receiving inputs from A beta- A delta- and C-fibre afferents were monitored. At all time points, there was a significant increase in the ongoing activity of deep dorsal horn neurones when compared to nai ve rats, correlating well with the behavioural hypersensitivity. Both the magnitude of neuronal responses, and the proportion of neurones responding to electrical or mechanical stimulation in an area of secondary hypersensitivity, were significantly increased 4-8 and 13-17 days following FCA injection. However, while there was still behavioural hypersensitivity at 55-59 days there was a substantial decline in the responses to mechanical stimulation and A-fibre responses to electrical stimulation, although the proportion of neurones responding in the C-fibre latency remained elevated. These results suggest that the behavioural hypersensitivity is due to hyperexcitability at the level of the dorsal horn reflected as an increase of both C-fibre responses and spontaneous activity. 10.1016/j.pain.2007.03.006
Activation of normal and inflamed fine articular afferent units by serotonin. Herbert M K,Schmidt R F Pain In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages. 10.1016/0304-3959(92)90115-R
Capsaicin suppresses substance P-induced joint inflammation in the rat. Lam F Y,Ferrell W R Neuroscience letters Intra-articular injection of 20 micrograms substance P in rat knee joints results in a pronounced inflammatory response. However, prior intra-articular injection of 1% capsaicin solution (1-5 weeks previously) virtually abolishes this response. This is not a neurotoxic effect of capsaicin on nerve fibres as denervation of the knee produces no alteration of the response to injected substance P. The potent effect of capsaicin on substance P-mediated inflammation cannot be attributed to depletion of mast cells by this treatment as the mast cell degranulator compound 48/80 injected into capsaicin pre-treated knees still gives rise to a marked inflammatory response. Compound 48/80 does not activate nerve fibres to cause release of substance P as it is equally effective in eliciting an inflammatory response in the presence of 100 micrograms of the substance P antagonist D-Pro4, D-Trp7,9,10 SP(4-11) in the synovial cavity. The results suggest that capsaicin may act by depleting substance P receptors in joint tissue. 10.1016/0304-3940(89)90028-1
Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis. International journal of molecular sciences -based terpenes are believed to modulate physiological responses to disease and alter the efficacy of cannabinoids in the so-called "entourage effect". The monoterpene myrcene can reduce nociception produced by noxious thermal and mechanical stimuli as well as reducing acute inflammation. The current study examined the role of myrcene and cannabidiol (CBD) in controlling chronic joint inflammation and pain. Chronic arthritis was induced in male Wistar rats by intra-articular injection of Freund's complete adjuvant into the right knee. On days 7 and 21 after arthritis induction, joint pain (von Frey hair algesiometry), inflammation (intravital microscopy, laser speckle contrast analysis) and joint histopathology were assessed. Local application of myrcene (1 and 5 mg/kg s.c.) reduced joint pain and inflammation via a cannabinoid receptor mechanism. The combination of myrcene and CBD (200 μg) was not significantly different from myrcene alone. Repeated myrcene treatment had no effect on joint damage or inflammatory cytokine production. These data suggest that topical myrcene has the potential to reduce chronic arthritis pain and inflammation; however, it has no synergistic effect with CBD. 10.3390/ijms23147891
NF-κB Phosphorylation Inhibition Prevents Articular Cartilage Degradation in Osteoarthritis Rats via 2-Aminoquinoline. He Jinlong,Zheng Shicheng Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Osteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model. MATERIAL AND METHODS The rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection. RESULTS The 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-kappaB) was markedly higher in the untreated rats. However, activation of NF-kappaB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline. CONCLUSIONS The present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-kappaB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis. 10.12659/MSM.920346
Time course and substance P effects on the vascular and morphological changes in adjuvant-induced monoarthritic rats. Lam Francis F Y,Wong Hilda H L,Ng Ethel S K International immunopharmacology The aim of this study is to characterize the time course of the vascular and morphological changes in arthritic rat knee joints induced by Freund's complete adjuvant (FCA), and to investigate the effects of substance P on these changes. Single unilateral intra-articular injections of 0.1 ml FCA produced swelling of the ipsilateral knees for 4 weeks, blood vessel permeability was increased for 1 week, but blood flow was unaffected except for minor bilateral increases on day 28. The ipsilateral knees also showed marked accumulation of immune cells from day 3 to day 28, minor synovial tissue proliferation on week 2, and some cartilage erosions on weeks 1 and 2. Another group of rats was given additional injection of 1 nmol substance P in their adjuvant-treated knees at 4 h prior to assessments of inflammatory parameters on each specified day. This produced further swelling in their ipsilateral knees on day 3 and day 14, blood vessel permeability was augmented in the first 2 weeks, and blood flow was increased throughout the 4 weeks except on day 7. Parallel but smaller increases in vascular permeability and blood flow were also observed in their contralateral knees. Substance P did not affect FCA-induced changes in immune cell infiltration, synovial tissue proliferation, and cartilage erosion. These findings confirm that intra-articular injection of a low dose of FCA could elicit discrete monoarthritis in rat knees, and substance P could exacerbate and spread the early signs of this disease to the contralateral knees. 10.1016/j.intimp.2004.01.009
Changes in vascular porosity and joint blood flow during development of collagen induced arthritis in the rat. Modulation by indomethacin and L-NAME. Andersson S E,Ekström G M The Journal of rheumatology OBJECTIVE:To investigate changes in regional blood flows (RBF) and vascular porosity during the early phase of the autologous collagen II induced arthritis model (CIA) in rats and the possible influence of indomethacin and nitric oxide (NO) synthase on these variables. METHODS:RBF was measured with the microsphere method and vascular porosity by determination of extravasation of radiolabeled albumin. RESULTS:Onset of arthritis was associated with a rapid increase in vascular porosity in the knee. In ankles and paws this increase was somewhat slower in onset, but progressed during the course of the study. Acute treatment with indomethacin reduced albumin extravasation in the knees, but had no effect in the ankles or paws. Similarly, chronic indomethacin treatment also had no effect on the arthritic score. Serum levels of nitrite/nitrate did not change markedly during the development of CIA, and NO synthase inhibition did not affect the vascular porosity. The changes in RBF were relatively modest. In most tissues the total RBF increased with increasing tissue weight. Pretreatment with indomethacin reduced RBF in the paws, but not in the periarticular tissue. CONCLUSION:The development of CIA is characterized by a marked rise in vascular porosity in affected joints, but the changes in RBF are much smaller and nonpersistent. The leakiness seems to be insensitive to the modulation of RBF and the responses in the knee show different characteristics compared to those in the ankle/paw.
Neurogenic influences on contralateral responses during experimental rat monoarthritis. Kidd B L,Cruwys S C,Garrett N E,Mapp P I,Jolliffe V A,Blake D R Brain research Many inflammatory conditions show topographically precise symmetrical responses. In this study we assessed vascular and cellular responses of apparently normal knees following induction of monoarthritis on the opposite side. A strictly localised monoarthritis was induced in the right knee of experimental animals using intra-articular latex spheres. In both knee joints bradykinin-induced plasma extravasation was significantly enhanced increasing from 0.52 +/- 0.07 micrograms/ml Evans blue to 0.99 +/- 0.07 micrograms/ml and 0.88 +/- 0.1 micrograms/ml in the injected and uninjected, contralateral, knees respectively (P < 0.05). A bilateral increase in cellularity was also apparent with cell counts in the uninjected, and apparently normal, knee increasing from 512 +/- 42 cells/mm2 to a maximum of 812 +/- 125 cells/mm2 on day 10 (P < 0.05). Immunohistological analysis demonstrated that the infiltrating cells in both the ipsilateral and contralateral joints were predominantly macrophages. Cell counts were not increased in the other peripheral joints. Levels of the sensory neuropeptide substance P were significantly elevated in both the ipsilateral and contralateral dorsal root ganglia and prior inhibition of small unmyelinated nerve activity inhibited the cellular infiltrate on the contralateral side, suggesting that the effect was mediated, at least partially, by a specific neurogenic pathway. The data suggests the presence of a neurogenic mechanism able to induce a topographically precise response. This may serve to upregulate the cellular defences of at-risk tissues following a potentially damaging stimulus at another site. 10.1016/0006-8993(95)00512-o
Quality of life and functional outcomes with tapentadol prolonged release in chronic musculoskeletal pain: analysis. Ferri Cesar Margarit,Natoli Silvia,Sanz-Ayan Paz,Magni Alberto,Guerrero Carlos,Lara-Solares Argelia,Liedgens Hiltrud,Thömmes Guido,Karra Ravi Pain management To investigate quality of life (QOL) and functionality changes in chronic pain during tapentadol prolonged release (PR) treatment. analysis of data from three Phase III trials in patients with osteoarthritis knee pain or low back pain. QOL and functionality changes were assessed by SF-36 scores. All SF-36 subdomain scores improved progressively to week 3 of tapentadol titration and were sustained during 12-week maintenance treatment. Improvements in SF-36 scores were similar between tapentadol dose groups (e.g., 200 to <300 mg vs ≥500 mg), with no greater effect from higher doses. QOL and functionality improvements were consistently greater with tapentadol PR than oxycodone controlled release. Tapentadol PR provides consistent, clinically relevant improvements in QOL and functionality in chronic pain. 10.2217/pmt-2020-0084
Topical ketanserin attenuates hyperalgesia and inflammation in arthritis in rats. Hong Yanguo,Ji Haiming,Wei Hua Pain We investigated effects of topical application of ketanserin, a 5-HT2A receptor antagonist, on hyperalgesia and edema in the arthritic rat, a chronic pain model with inflammation. Unilateral, but not bilateral, arthritis was induced with intra-articular injection of a mixture of kaolin and carrageenan in one side, as indicated by the shortened paw withdrawal latency and an increase in the circumference of the knee joint. Topical application of ketanserin onto skin over the arthritic joint delivered in a mixture of gelatin, glycerol and kaolin produced dose-dependent attenuation of nociceptive and inflammatory effects resulting from intra-articularly injected kaolin/carrageenan. One and 3% ketanserin produced significant or even complete anti-hyperalgesia, as well as a remarkable anti-inflammatory effect (50-70% reduction of edema) while 0.3% ketanserin and placebo failed to produce any effect. Moreover, the effects of ketanserin were maintained for 13 days without decline. In contrast, 3% ketanserin applied to skin of the knee joint on the non-inflamed side for 2 weeks did not alter nociceptive thresholds of the paw and the size of the knee joint in both the inflamed and non-inflamed limbs. These results indicate that 5-HT2A receptors in the periphery play a significant role in the maintenance and/or development of inflammatory pain. The present study suggests that topical ketanserin is a promising direction for potential clinical exploration to relieve established hyperalgesia and inflammation in arthritis without adverse effects and tolerance. 10.1016/j.pain.2006.03.010
Prolonged alteration of vasoconstrictor and vasodilator responses in rat knee joints by adjuvant monoarthritis. McDougall J J,Karimian S M,Ferrell W R Experimental physiology Both neurogenic influences and the regulatory neuropeptide substance P (SP) have been implicated in the development of joint inflammation. Using the laser Doppler perfusion imaging technique to quantify relative changes in joint blood flow, the effects of nerve stimulation and topical SP application were examined in normal and chronically inflamed rat knee joints. Synovial inflammation was induced by unilateral intra-articular injection of Freund's complete adjuvant and experiments were carried out 1 week and 3 weeks later. Normal knees showed a frequency-dependent vasoconstriction in response to saphenous nerve stimulation over the range of 5-30 Hz and a dose-dependent vasodilation in response to SP administration. These vasoactive responses were completely abolished in the chronically inflamed knee joint, the abolition persisting throughout the investigation. Since articular cartilage is critically dependent on synovial fluid formation for its nutrition, loss of neurovascular control of the synovial microcirculation could contribute to the degenerative changes that commonly accompany chronic inflammatory joint diseases. 10.1113/expphysiol.1995.sp003852
[Analgesic placebo effect: contribution of the neurosciences]. Berna C,Cojan Y,Vuilleumier P,Desmeules J Revue medicale suisse Over the past twenty years, neuroscience has changed our understanding of placebo analgesia. Often perceived by researchers as a response bias adding noise to the assessment of efficacy, in the patients' view, it is associated with charlatanism. The origin of the word, qualifying a patient's response to "please" the doctor, did not help its rightful appreciation. However, today the placebo analgesia is considered as a psychobiological phenomenon. Thanks to pharmacological manipulations and the development of functional brain imaging, the neural circuitry involved in this effect as well as the role of endorphins and dopamine have been identified. This article describes our current knowledge about this fascinating phenomenon: a psychological modulation can lead to a biological effect.
Acute joint inflammation alters the adrenoceptor profile of synovial blood vessels in the knee joints of rabbits. Annals of the rheumatic diseases Experiments were carried out to examine the effect of acute inflammation, induced by intra-articular injection of 2% carrageenan, on the response of articular blood vessels in the knee joints of rabbits to adrenoceptor agonists. The responses to noradrenaline, phenylephrine, clonidine, UK-14304, and isoprenaline were examined 24 hours after carrageenan injection and compared with those of normal animals. Antagonists specific for alpha 1 and alpha 2 were used to identify the adrenoceptors through which the responses were mediated and to examine if carrageenan treatment altered the adrenoceptor profile of these blood vessels. The evidence suggests that in the carrageenan treated animals there is a reduction in the alpha 1 response with an associated increase in the alpha 2 response. A decrease in the number or affinity of alpha 1 adrenoceptors is indicated by the shift to the right of the noradrenaline and phenylephrine dose/response curves, whereas an increase in alpha 2 affinity or number is suggested by the associated leftward shift in the alpha 2 adrenoceptor agonist curves. This change in receptor profile appears to arise as a direct result of carrageenan induced joint inflammation. 10.1136/ard.51.10.1129
Lycopene inhibits IL-1β-induced inflammation in mouse chondrocytes and mediates murine osteoarthritis. Zhan Jingdi,Yan Zijian,Kong Xiaojiang,Liu Junling,Lin Zeng,Qi Weihui,Wu Yifan,Lin Jian,Pan Xiaoyun,Xue Xinghe Journal of cellular and molecular medicine Osteoarthritis (OA) is a common chronic degenerative condition in the elderly, in which inflammation plays a key role in disease pathology. Lycopene (Lye), a member of the carotenoid family, has been reported to have anti-inflammatory effects. The purpose of this study was to investigate the effect of Lye on the inflammation of chondrocytes and the mouse OA model. Chondrocytes were treated with interleukin (IL)-1β, and the mouse OA model was induced by the surgical destabilization of the medial meniscus (DMM). The results showed that Lye could inhibit the expression of inflammatory factors and alleviate the degradation of extracellular matrix (ECM). Additionally, Lye could activate the Nrf2/HO-1 pathway and reverse the activations of NF-κB and STAT3 signal pathway induced by IL-1β, suggesting that its anti-inflammatory effect may be mediated via these pathways. The animal experiments showed that Lye could decrease the Osteoarthritis Research Society International (OARSI) scores of the knee, indicating that it could inhibit the occurrence and development of OA in mouse. Overall, our results indicated that Lye might be used as a novel drug for OA treatment. 10.1111/jcmm.16443
Neural changes in acute arthritis in monkeys. III. Changes in substance P, calcitonin gene-related peptide and glutamate in the dorsal horn of the spinal cord. Sluka K A,Dougherty P M,Sorkin L S,Willis W D,Westlund K N Brain research. Brain research reviews The effects of an experimentally induced arthritis on immunoreactivity of putative primary afferents neurotransmitter/neuromodulators were examined. Immunoreactive staining for substance P (SP), calcitonin gene-related peptide (CGRP) and glutamate (Glu) in the monkey dorsal horn was examined following inflammation of one knee joint induced by injection of 5% kaolin and 5% carrageenan. Spinal cords were examined at different time periods after induction of arthritis (2.5, 4, 6 and 8 h). Side to side differences in immunoreactivity were determined by a computer assisted quantitation system. A significant overall decrease in immunoreactivity of the lumbar versus the cervical dorsal horn was found for SP. The decrease for SP showed maximal changes of 68.3% at 4 h and 54.7% at 6 h. Immunoreactivity for CGRP was decreased 31.5% at 8 h and variable at other time points. Immunoreactivity for Glu, showed an ipsilateral increase of 31.4% at 4 h, 33.7% at 6 h, 39.9% at 8 h and a significant effect for lumbar versus cervical. Repetitive peripheral stimulation of the joint was shown to be important for changes in SP and Glu immunoreactivity. Without frequent peripheral stimulation in the early stages of the development of arthritis, SP showed no quantitative side to side differences. Increases in Glu immunoreactivity were present but not as prominent with minimal joint manipulation. These studies suggest that Glu may be involved in the aching pain of inflammation at rest whereas SP, CGRP and Glu may mediate pain induced by joint movement. 10.1016/0165-0173(92)90004-6
[Mechanism of thermosensitive moxibustion on knee osteoarthritis in rabbit models]. Fu Yong,Chen Shutao,Mao Jiaona,Pan Yi,Huang Chao,Xiong Jun,Yan Chunchuan,Huang Xiaodong,Zhang Haifeng Zhongguo zhen jiu = Chinese acupuncture & moxibustion OBJECTIVE:To observe the impacts of thermosensitive moxibustion (TSM) on the expressions of nitric oxide (NO), typeⅠdisintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), typeⅡcollagen and proteoglycan (PG) in the rabbit models of knee osteoarthritis (KOA) and explore the mechanism of TSM on KOA. METHODS:A total of 42 Japanese long-eared male rabbits were divided into a blank group (6 rabbits), a model group (6 rabbits), a moxibustion group (24 rabbits) and a sham-operation group (6 rabbits) according to the random number table. In the blank group, the rabbits were fed normally. In the model and moxibustion groups, the papain injection was given to establish KOA models. The rabbits in the sham-operation group were treated with the intracavity injection of 0.9% NaCl solution. The rabbits were forced to move for 30 min every day, continuously for 15 days during modeling. At the end of modeling, in the moxibustion group, moxibusiton was applied at "Dubi" (ST 35), once a day, 40 min each time, for 14 days totally. According to the temperature changes during moxibustion, the rabbits were divided into a TSM group and a non-TSM group. 6 rabbits were collected randomly from the two groups. The usual feeding was given in the blank group, the model group and the sham-operation group, without any intervention. The body mass and behavioristics changes were observed in each group. At the end of treatment, the nitrate reduction method was adopted to determine NO expression in the serum. The real-time PCR was adopted to determine the expressions of ADAMTS-4, typeⅡcollagen and PG in the cartilage. RESULTS:① After modeling, compared with the blank group, the body mass was all reduced and the Lequesne MG score was increased in the model group, TSM group, non-TSM group and sham-operation group (<0.05, <0.01). After intervention, compared with the blank group, the body mass was decreased and the Lequesne MG score was increased in the model and sham-operation groups (<0.05, <0.01). Compared with the model group, the body mass was increased and the lequesne MG score was decreased in the TSM, non-TSM, and sham-operation groups (<0.05, <0.01). Compared with the non-TSM group, the body mass in the TSM group was increased remarkably (<0.05), but the difference in Lequesne MG score was not statistically significant (>0.05). ② After intervention, compared with the blank group, the expressions of NO and ADAMTS-4 were all increased and the expressions of typeⅡcollagen and PG were decreased in the model group, TSM group, non-TSM group and sham-operation group (<0.05, <0.01). Compared with the model group, the expressions of NO and ADAMTS-4 were all remarkably lower and the expressions of typeⅡcollagen and PG were increased in the TSM group, non-TSM group and sham-operation group (<0.05, <0.01). Compared with the non-TSM group, the expressions of NO and ADAMTS-4 were all remarkably lower and the expressions of typeⅡcollagen and PG were increased in the TSM group after intervention (all <0.05). CONCLUSION:The thermosensitive moxibustion alleviates the inflammatory reactions and protects the joint cartilage through inhibiting the expressions of NO and ADAMTS-4 to achieve the effects in the treatment of KOA. 10.13703/j.0255-2930.2018.03.017
Central terminals of nociceptors are targets for nicotine suppression of inflammation. Miao F J P,Green P G,Benowitz N,Levine J D Neuroscience Spinal intrathecal administration of nicotine inhibits bradykinin-induced plasma extravasation, a component of the inflammatory response, in the knee joint of the rat in a dose-related fashion. Nociceptors contain nicotinic receptors and activation of a nociceptor at its peripheral terminal, by capsaicin, also produces inhibition of inflammation. Therefore the aim of this study was to test the hypothesis that the spinal target for this effect of nicotine is the central terminal of the primary afferent nociceptor. Intrathecal administration of the neurokinin-1 receptor antagonist, (3aR,7aR)-7,7-diphenyl-2-(1-imino-2(2-methoxyphenyl)-ethyl) perhydroisoindol-4-1 hydrochloride or the N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonovaleric acid, both antagonists of the action of primary afferent neurotransmitters, markedly attenuated the inhibition of bradykinin-induced plasma extravasation produced by both intrathecal nicotine and intraplantar capsaicin.Conversely, intrathecal administration of an alpha-adrenoceptor antagonist, phentolamine or an opioid receptor antagonist, naloxone, to block descending antinociceptive controls, which provide inhibitory input to primary afferent nociceptors, enhanced the action of both nicotine and capsaicin. These findings support the hypothesis that the central terminal of the primary afferent nociceptor is a CNS target at which nicotine acts to inhibit inflammation. 10.1016/j.neuroscience.2003.10.027
Factors related to degradation of articular cartilage in osteoarthritis: a review. Tanaka S,Hamanishi C,Kikuchi H,Fukuda K Seminars in arthritis and rheumatism OBJECTIVES:Osteoarthritis (OA) is a common joint deterioration initiated by multiple factors. To better understand related factors in the development of this disease, we focused on the mechanical stress loaded on articular cartilage. MATERIALS AND METHODS:The anterior cruciate ligaments of rabbit knee joints were transected, and expression of protein kinase C (PKC) examined immunohistochemically. The PKC activator 12-o-tetradecanoyl-phorbol-13-acetate (TPA) was then administered intraarticularly. To determine the involvement of gas mediators, a cartilage defect was made on the medical femoral condyle of rabbit knee joints. Hydrostatic pressure was loaded on the cartilage taken from the surrounding defects, and levels of superoxide anion and nitric oxide (NO) were measured. Bovine chondrocytes were subjected to cyclic mechanical stretch using a Flexercell Strain Instrument. Proteoglycan synthesis and PKC activity were measured. Expression of matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 in articular cartilages obtained from OA patients were examined using Northern blots. RESULTS:Chondrocytes from experimentally induced OA were stained positively with anti-alpha-PKC antibody. Intraarticular administration of TPA prevented the development of OA changes. Cyclic tensile stretch loaded on chondrocytes decreased proteoglycan synthesis and PKC activity. Thus, PKC is involved in the stress-mediated degradation of articular cartilage. Cartilage defects led to degradation of surrounding cartilage and to enhanced superoxide anion and NO synthesis. We also noted increased and decreased expressions of MMP-3 and TIMP-1 mRNA in human OA cartilage, respectively. CONCLUSION:PKC, gas mediators (superoxide anion, NO), and proteinases are all involved in OA. 10.1016/s0049-0172(98)80019-x
Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice. van de Loo F A,Kuiper S,van Enckevort F H,Arntz O J,van den Berg W B The American journal of pathology Using interleukin (IL)-6-deficient (IL-6(0/0) mice or wild-type mice, we investigated the controversial role of IL-6 in joint inflammation and cartilage pathology during zymosan-induced arthritis (ZIA). Monoarticular arthritis was elicited by injection of zymosan into the right knee joint cavity. Production of IL-1, tumor necrosis factor (TNF), IL-6, and nitric oxide by the inflamed knee was assessed in washouts of joint capsule specimens. Plasma corticosterone was measured using a radioimmunoassay. Proteoglycan synthesis was assessed using [35S]sulfate incorporation into patellas ex vivo. Joint swelling was quantified by joint uptake of circulating 99mTechnetium pertechnetate. Histology was taken to evaluate cellular infiltration and cartilage damage. Zymosan caused a rapid increase in articular IL-1, IL-6, TNF, and NO levels. Except for IL-6, the released amounts and time course of these mediators were comparable in the IL-6-deficient mice and the wild-type mice. Elevated plasma corticosterone levels were measured during the first day of arthritis in both strains. At day 2 of ZIA, joint inflammation (joint swelling and cell exudate) in IL-6-deficient mice was comparable with that in the wild-type mice. The marked suppression of chondrocyte proteoglycan synthesis and proteoglycan degradation were on the average higher in the IL-6-deficient mice. Together this resulted in a more pronounced proteoglycan depletion in the IL-6-deficient mice as compared with the wild-type mice during the first week of arthritis. Injection of recombinant IL-6 into the joint cavity corrected the IL-6 deficiency and significantly reduced cartilage destruction. Inflammation was more chronic in the wild-type mice, and these mice also showed a higher prevalence for osteophyte formation. In ZIA, IL-6 plays a dual role in connective tissue pathology, reducing proteoglycan loss in the acute phase and enhancing osteophyte formation in the chronic phase. The latter could be related to the more severe joint inflammation as seen in the normal (IL-6-producing) animals during the chronic phase of arthritis.
Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat. Hong Seung Kil,Han Jeong Seok,Min Sun Seek,Hwang Jong Moon,Kim Yang In,Na Heung Sik,Yoon Young Wook,Han Hee Chul Neuroscience letters Substance P is known to exert various pro-inflammatory effects that are mediated by neurokinin-1 (NK-1) receptor in peripheral tissues. This study examined the effect of the NK-1 receptor antagonist cis-2-[diphenylmethyl]-N-[(2-iodophenyl)-1-azabicyclo[2.2.2]octan-3-amine] (L-703,606) on nociceptive response following carrageenan injection (2%, 50 microl) into the knee joint cavity of the right hind leg. L-703,606 injection (0.1 or 1 mM, 50 microl) into the same joint cavity immediately before the carrageenan injection significantly reduced the nociceptive response. However, antagonist treatment at 5 h after carrageenan injection was ineffective in alleviating nociception. Neither intraperitoneal injection of the antagonist (1 mM, 50 microl) immediately before the carrageenan injection was effective. These results suggest that local NK-1 receptor contributes to the induction, but not maintenance, of arthritic pain. 10.1016/s0304-3940(02)00070-8
Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis. Ashraf Sadaf,Bouhana Karyn S,Pheneger Jed,Andrews Steven W,Walsh David A Arthritis research & therapy BACKGROUND:Inflammation is an essential component of arthritis pain. Nerve growth factor (NGF) plays a key role in acute and chronic pain states especially those associated with inflammation. NGF acts through tropomyosin-receptor-kinase A (TrkA). NGF blockade has reduced arthritis pain in clinical trials. We explored the mechanisms within the joint which may contribute to the analgesic effects of NGF by selectively inhibiting TrkA in carrageenan-induced or collagen-induced joint pain behaviour. The goal of the current study was to elucidate whether inflammation is central to the efficacy for NGF blockade. METHODS:Rats were injected in their left knees with 2 % carrageenan or saline. Collagen-induced arthritis (CIA) was induced by intradermal injections of a mixture of bovine type II collagen (0.2 mg) and incomplete Freund's adjuvant (0.2 mg). Oral doses (30 mg/kg) of AR786 or vehicle control were given twice daily after arthritis induction. Ibuprofen-treated (35 mg/kg, orally, once daily) rats with CIA were used as positive analgesic controls. Pain behaviour was measured as hind-limb weight-bearing asymmetry and hind-paw withdrawal thresholds to von Frey hair stimulation (carrageenan synovitis), or withdrawal to joint compression using a Randall Selitto device (CIA). Inflammation was measured as increased knee joint diameter and by histopathological analysis. RESULTS:Intra-articular injections of carrageenan or induction of CIA was each associated with pain behaviour and synovial inflammation. Systemic administration of the TrkA inhibitor AR786 reduced carrageenan-induced or CIA-induced pain behaviour to control values, and inhibited joint swelling and histological evidence of synovial inflammation and joint damage. CONCLUSIONS:By using two models of varying inflammation we demonstrate for the first time that selective inhibition of TrkA may reduce carrageenan-induced or CIA-induced pain behaviour in rats, in part through potentially inhibiting synovial inflammation, although direct effects on sensory nerves are also likely. Our observations suggest that inflammatory arthritis causes pain and the presence of inflammation is fundamental to the beneficial effects (reduction in pain and pathology) of NGF blockade. Further research should determine whether TrkA inhibition may ameliorate human inflammatory arthritis. 10.1186/s13075-016-0996-z
Inhibitory effect of somatostatin on the mechanosensitivity of articular afferents in normal and inflamed knee joints of the rat. Heppelmann Bernd,Pawlak Matthias Pain The effect of somatostatin on the sensory activity of primary afferents was studied in normal and acutely inflamed rat knee joints. Fine afferent nerve fibers with conduction velocities of 0.9-18.0 m/s were recorded as single units. All nerve fibers tested responded to local mechanical stimulation, movements of the joint and i.a. injections of KCl (10(-4) mol, 0.1 ml) close to the joint. Somatostatin (10(-4) mol, 0.2 ml) caused no direct response of the units. In normal joints, somatostatin did not change the discharges evoked by non-noxious movements but decreased the responses to noxious movements significantly to about 63% of the responses before the application. In acutely inflamed joints, somatostatin reduced the discharges of non-noxious and of noxious movements to about 55% and 52%, respectively. Injections of somatostatin with lower concentrations (10(-6) mol, 10(-8) mol) i.a. close to inflamed joints revealed shorter and less pronounced reductions of the responses to noxious movements. In a proportion of afferents, substance P (10(-4) mol) and bradykinin (10(-4) mol) were able to increase these responses again. These data indicate that the mechanosensitivity of articular afferents in normal joints may also be regulated by several neuropeptides based on a balance of pro-inflammatory peptides such as substance P, and anti-inflammatory peptides such as somatostatin. In an inflamed joint, pro-inflammatory peptides seem to predominate resulting in a sensitization of the peripheral nerve fibers. In this case, an application of somatostatin or its analogues could be used clinically to compensate this effect. 10.1016/S0304-3959(97)00124-3
Duloxetine ameliorates the impairment of diffuse noxious inhibitory control in rat models of peripheral neuropathic pain and knee osteoarthritis pain. Yoneda Sosuke,Kasai Erika,Matsuo Midori,Tamano Ryuta,Sakurai Yusuke,Asaki Toshiyuki,Fujita Masahide Neuroscience letters Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2 mg monoiodoacetate (MIA), respectively. Capsaicin (30-100 μg/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30 μg and reached its maximal level at 100 μg. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10 mg/kg). The oral administrations of pregabalin (10 mg/kg) and celecoxib (3 mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway. 10.1016/j.neulet.2020.134990
Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRbeta tyrosine phosphorylation. Studer R K,Levicoff E,Georgescu H,Miller L,Jaffurs D,Evans C H American journal of physiology. Cell physiology Chondrocytes in arthritic cartilage respond poorly to insulin-like growth factor I (IGF-I). Studies with inducible nitric oxide synthase (iNOS) knockout mice suggest that NO is responsible for part of the cartilage insensitivity to IGF-I. These studies characterize the relationship between NO and chondrocyte responses to IGF-I in vitro, and define a mechanism by which NO decreases IGF-I stimulation of chondrocyte proteoglycan synthesis. Lapine cartilage slices, chondrocytes, and cartilage from osteoarthritic (OA) human knees were exposed to NO from the donors S-nitroso-N-acetylpenicillamine (SNAP) or (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate] (DETA NONOate), by transduction with adenoviral transfer of iNOS (Ad-iNOS), or by activation with interleukin-1 (IL-1). NO synthesis was estimated from medium nitrite, and proteoglycan synthesis was measured as incorporation of (35)SO(4). IGF-I receptor phosphorylation was evaluated with Western analysis. SNAP, DETA NONOate, endogenously synthesized NO in Ad-iNOS-transduced cells, or IL-1 activation decreased IGF-I-stimulated proteoglycan synthesis in cartilage and monolayer cultures of chondrocytes. OA cartilage responded poorly to IGF-I; however, the response to IGF-I was restored by culture with N(G)-monomethyl-L-arginine (L-NMA). IGF-I receptor phosphotyrosine was diminished in chondrocytes exposed to NO. These studies show that NO is responsible for part of arthritic cartilage/chondrocyte insensitivity to anabolic actions of IGF-I; inhibition of receptor autophosphorylation is potentially responsible for this effect. 10.1152/ajpcell.2000.279.4.C961
Reactions of cardiac postganglionic sympathetic neurons to movements of normal and inflamed knee joints. Sato Y,Schaible H G,Schmidt R F Journal of the autonomic nervous system The effects of passive movements of normal and inflamed knee joints on unitary activity in filaments of the inferior cardiac nerve (ICN) were studied in cats anesthetized with chloralose and urethane. The effects were compared with those obtained by electrical stimulation of afferent A- and C-fibers in the medial articular nerve, in muscle and in cutaneous hind limb nerves. The vagus nerves were cut and the right carotid artery was tied off. The left carotid sinus was intact. All ICN units used in this study displayed spontaneous activity which was usually related to the cardiac and respiratory rhythms. The ICN units were regularly excited by electrically evoked single or short repetitive A-volleys in articular, cutaneous and muscle nerves. The excitation was followed by a silent period. Inclusion of C-fibers in the afferent volleys gave a second, long-latency burst of impulses which was seen only with short repetitive stimulation. Passive movements in the normal working range of the joint did not influence the activity of ICN units. However, noxious joint movements, particularly of inflamed joints, led to pronounced excitation of ICN units accompanied by rises in blood pressure. Most of these effects could still be seen after all nerves to the hind limbs, except the medial articular nerve, were cut. It is proposed (a) that ICN units form a homogeneous population of sympathetic postganglionic units whose reaction pattern to somatovisceral input is distinctly different from that of other sympathetic subsystems, and (b) that articular receptors make a substantial contribution to the ICN input particularly when many fine afferent units are sensitized to mechanical stimulation by an acute joint inflammation.
The safety of intra-articular injections for the treatment of knee osteoarthritis: a critical narrative review. Nguyen Christelle,Rannou François Expert opinion on drug safety INTRODUCTION:International guidelines recommend that the management of knee osteoarthritis (OA) combine both nonpharmacological and pharmacological interventions. Intra-articular (IA) therapies are considered part of this multimodal approach and are well-established Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved treatments. Areas covered: Safety data for knee OA, including IA corticosteroids, hyaluronic acid, platelet-rich plasma and botulinum toxin are critically reviewed, and evidence- and pratice-based measures to improve safety of IA therapies are discussed. Expert opinion: The incidence of AEs attributable to IA therapies across clinical trials in knee OA is very low, and barely reaches significance when compared to the incidence of AEs in the comparator group. These events are exceptionally serious. Mild differences between products have been inconsistently reported mainly for IA HA. One can distinguish self-limited AEs such as post-injection pain and swelling that are the most frequently reported AEs, from AEs that are not self-limited but rare such as septic arthritis. The safety of IA therapies can be improved by applying simple measures designed to prevent AEs. However, even though no specific safety concerns have been raised to date about IA therapies, the quality of evidence is low, and there is a need to improve the monitoring and reporting of safety data from clinical trials and post-marketing surveillance. 10.1080/14740338.2017.1344211
Neural changes in acute arthritis in monkeys. II. Increased glutamate immunoreactivity in the medial articular nerve. Westlund K N,Sun Y C,Sluka K A,Dougherty P M,Sorkin L S,Willis W D Brain research. Brain research reviews Glutamate and other excitatory amino acids have been shown to play a key role in nociception and the hyperalgesia associated with the acute inflammatory response. In an effort to understand more fully the role of Glu in this process, we determined that there is Glu in a percentage of axons in the medial articular nerve (MAN) of monkeys, a source of preterminal afferent fibers innervating the knee joint. After induction of the experimental knee joint inflammation with a kaolin/carrageenan mixture, comparison was made of the percentage of Glu positive axons in the MAN on the side of the inflammation versus the contralateral MAN using post-embedding immunogold electron microscopic methods. A doubling in the percentage of Glu-containing axons was observed on the side of the experimental arthritis as compared to the MAN of the other side or of uninjected controls. Glu positive axons were unmyelinated or were included in the small, thinly myelinated group in control nerves. Following induction of the inflammation, axonal diameter measurements revealed an increase in Glu content primarily in the small, thinly myelinated axons, which correspond to the group III afferent fibers. These increases were observed in the anesthetized preparation only when injection of kaolin/carrageenan was combined with joint flexion and mechanical stimulation. The dramatic increase in percentages of fibers stainable for Glu in the MAN following the induction of inflammation suggests that Glu content is greatly increased in the afferent fibers and may be a major contributor to the enhanced responses of sensory neurons in inflammatory states such as arthritis. 10.1016/0165-0173(92)90003-5
Different response of human chondrocytes from healthy looking areas and damaged regions to IL1β stimulation under different oxygen tension. Huang Xiaobin,Zhong Leilei,Hendriks Jan,Post Janine N,Karperien Marcel Journal of orthopaedic research : official publication of the Orthopaedic Research Society Due to its avascular nature, articular cartilage is relatively hypoxic. The aim of this study was to elucidate the functional changes of macroscopically healthy looking areas chondrocytes (MHC) and macroscopically damaged regions chondrocytes (MDC) at a cellular level in response to the inflammatory cytokine IL1β under different oxygen tension levels. In this study, two-dimensional (2-D) expanded MHC and MDC were redifferentiated in 3-D pellet cultures in chondrogenic differentiation medium, supplemented with or without IL1β at conventional culture (normoxia) or 2.5% O (hypoxia) for 3 weeks. qPCR, immunohistochemistry and ELISA were used to detect the expression of anabolic and catabolic gene expression. Alcian blue/Safranin O staining and GAG assay were used to measure cartilage matrix production. Cell proliferation and apoptosis were assessed by EdU staining and TUNEL assay, respectively. The results showed that hypoxia enhanced matrix production in both MHC and MDC and this effect was stronger on MDC. Under normoxia, MHC showed higher expression of cartilage markers and lower catabolic genes expression than MDC. Interestingly, hypoxia diminished the difference between MHC and MDC. IL1β potently induced MMPs expression regardless of cell population and oxygen tension. The fold induction of these MMPs in hypoxia was however much higher than in normoxia. In addition, hypoxia promoted the expression of HIF1α and HIF2α in MHC, while it only enhanced HIF1α expression but decreased the HIF2α expression in MDC. We concluded that hypoxia stimulated the redifferentiation of cultured chondrocytes, particularly in MDC derived from macroscopically diseased cartilage. Oxygen tension may profoundly and differentially influence inflammation-associated cartilage injury and diseases by regulating the expression of HIF1α and HIF2α. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX-XX, 2018. 10.1002/jor.24142
Stimulation of sensory neuropeptide release by nociceptin/orphanin FQ leads to hyperaemia in acutely inflamed rat knees. British journal of pharmacology The peripheral effect of the 'opioid-like' peptide nociceptin/orphanin FQ (N/OFQ) on joint blood flow was investigated in acutely inflamed rats. Sensory neuropeptide release from capsaicin-sensitive nerves and the involvement of synovial mast cells and leukocytes on these vasomotor responses were also studied. Blood flow measurements of exposed knee joints were performed in urethane-anaesthetised rats (2 mg kg(-1) intraperitoneal) using laser Doppler perfusion imaging. Topical administration of N/OFQ (10(-13)-10(-8) mol) to acutely inflamed joints caused a dose-dependent increase in synovial perfusion with an ED(50) of 4.0 x 10(-10) mol. This vasodilatatory response was blocked by the selective NOP receptor antagonist [Phe(1)-(CH(2)-NH)-Gly(2)]-Nociceptin(1-13)-NH(2) (10(-9) mol) (P<0.0001).Co-administration of N/OFQ with the neurokinin-1 (NK(1)) receptor antagonist [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-Substance P (10(-12) mol), the vasoactive intestinal peptide (VIP) receptor antagonist VIP(6-28) (10(-9) mol) or the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) (10(-9) mol) all blocked the hyperaemic effect of N/OFQ (P<0.0001). Treatment of acutely inflamed knees with capsaicin (8-methyl-N-vanillyl-6-noneamide) to destroy unmyelinated joint afferents also inhibited N/OFQ vasomotor activity. Stabilisation of synovial mast cells with disodium cromoglycate (cromolyn) ameliorated N/OFQ responses, whereas inactivation of circulating leukocytes with the pan-selectin inhibitor fucoidin completely blocked N/OFQ-induced hyperaemia in these joints. These experiments show that in acutely inflamed knee joints, N/OFQ acts on NOP receptors located on synovial mast cells and leukocytes leading to the secondary release of proinflammatory mediators into the joint. These agents subsequently stimulate sensory neuropeptide release from capsaicin-sensitive nerves culminating in vasodilatation and increased articular blood flow. 10.1038/sj.bjp.0706804
Muscle weakness causes joint degeneration in rabbits. Rehan Youssef A,Longino D,Seerattan R,Leonard T,Herzog W Osteoarthritis and cartilage OBJECTIVE:The objective of this study was to investigate the effects of botulinum toxin type-A (BTX-A) induced quadriceps weakness on micro-structural changes in knee cartilage of New Zealand White (NZW) rabbits. DESIGN:Fifteen rabbits were divided randomly into an experimental and a sham control group. Each group received a unilateral single quadriceps muscle injection either with saline (sham control; n=4) or BTX-A (experimental; n=11). RESULTS:BTX-A injection produced significant quadriceps muscle weakness (P<0.05) and loss of quadriceps muscle mass (P<0.05). Degenerative changes of the knee cartilage, assessed with the Mankin grading system, were the same for the injected and non-injected hind limbs of the experimental group animals. Sham injection had no effect on joint degeneration but all control animals showed some degenerative changes in the knee. Degenerative changes of the retro-patellar cartilage were more severe in the experimental compared to sham control group rabbits (P<0.05). The distal region of the retro-patellar cartilage was more degenerated than the proximal part in the experimental and control group rabbits (P<0.05). The Mankin grades for the tibiofemoral region were not significantly different between experimental and control group rabbits (P>0.05). CONCLUSION:Quadriceps muscle weakness caused increased degeneration in the retro-patellar cartilage of NZW rabbits, providing evidence that muscle weakness might be a risk factor for the onset and progression of osteoarthritis (OA). Future work needs to delineate whether muscle weakness directly affects joint degeneration, or if changes in function and movement execution associated with muscle weakness are responsible for the increased rate of OA onset and progression observed here. 10.1016/j.joca.2009.03.017
Responsiveness of vascular alpha1-adrenoceptors of diabetic rat knee joint to phenylephrine in acute inflammation. Hajizadeh S,Shiran K,Fathollahi Y Journal of basic and clinical physiology and pharmacology In diabetic angiopathy, responsiveness of alphal-adrenoceptors in blood vessels increases. The aim of this study was to investigate the vasoconstrictor response of knee joint blood vessels to phenylephrine (a 1-adrenoceptor agonist) in diabetes and acute inflammation. Acute knee joint inflammation was induced by the intraarticular injection of a 3% kaolin/3% carrageenan suspension. Diabetes was induced by the intravenous injection of alloxan (70 mg/kg). Male albino rats weighing 70 to 90 g each were divided into the following 4 groups: untreated controls, diabetic, inflammatory, and diabetic inflammatory. The blood flow of the knee joint was measured using the laser Doppler flowmetry (LDF) technique. Vasoconstriction of the articular microvascular was measured in response to the topical application of different concentrations (10(-7) to 10(-3) mol) phenylephrine. The results of this study show that (a) increased knee joint diameter and circumference due to inflammation and the knee joint basal blood flow were significantly lower in diabetic than in control rats; (b) the responsiveness of alphal-adrenoceptors decreased in kaolin/carrageenan-induced acute inflammation; (c) carrageenan-induced acute inflammation did not decrease the responsiveness of alphal-adrenoceptors in diabetic rats. We conclude that diabetes inhibits the reductive effect of acute inflammation on the responsiveness of alpha1-adrenoceptors in rats. 10.1515/jbcpp.2005.16.4.301
The neurokinin-1 receptor antagonist RP 67580 reduces the sensitization of primary afferents by substance P in the rat. Pawlak M,Schmidt R F,Heppelmann B,Hanesch U European journal of pain (London, England) The inflammatory mediator substance P (SP) produces a variety of biological effects in several tissues by binding to the tachykinin receptor neurokinin 1 (NK1) and, to a lesser extent, by binding to the neurokinin 2 receptor (NK2). To assess the sensitizing effect of SP on articular afferent fibres the NK1receptor antagonist RP 67580 was applied in normal and acutely inflamed rat knee joints. Altogether 38 fine afferent nerve fibres from the rat knee with conduction velocities of 0.71-13.5 m/s were recorded as single units, during non-noxious and noxious joint rotations. SP, injected i.a. as a bolus close to the knee joint, was able to sensitize 45.5% (10 of 22) of the units recorded from normal joints and 33.3% (five of 15) of afferents from inflamed joints. The following i.a. application of RP 67580 in a range of 20-200 nmol antagonized in a dose-dependent manner the sensitizing effect of SP in a large proportion of slowly conducting articular afferents from normal (66.7%) and inflamed (46.2%) knee joints. Subsequent SP application enhanced the afferent sensitivity further. The electrophysiological results presented here further support the suggestion that the sensitization of afferents by SP in the rat knee joint is mediated mainly by the NK1 receptor, which is probably located on the primary afferents. 10.1053/eujp.2000.0222
Are perioperative interventions effective in preventing chronic pain after primary total knee replacement? A systematic review. Beswick Andrew David,Dennis Jane,Gooberman-Hill Rachael,Blom Ashley William,Wylde Vikki BMJ open OBJECTIVES:For many people with advanced osteoarthritis, total knee replacement (TKR) is an effective treatment for relieving pain and improving function. Features of perioperative care may be associated with the adverse event of chronic pain 6 months or longer after surgery; effects may be direct, for example, through nerve damage or surgical complications, or indirect through adverse events. This systematic review aims to evaluate whether non-surgical perioperative interventions prevent long-term pain after TKR. METHODS:We conducted a systematic review of perioperative interventions for adults with osteoarthritis receiving primary TKR evaluated in a randomised controlled trial (RCT). We searched , MEDLINE, Embase, PsycINFO and CINAHL until February 2018. After screening, two reviewers evaluated articles. Studies at low risk of bias according to the Cochrane tool were included. INTERVENTIONS:Perioperative non-surgical interventions; control receiving no intervention or alternative treatment. PRIMARY AND SECONDARY OUTCOME MEASURES:Pain or score with pain component assessed at 6 months or longer postoperative. RESULTS:44 RCTs at low risk of bias assessed long-term pain. Intervention heterogeneity precluded meta-analysis and definitive statements on effectiveness. Good-quality research provided generally weak evidence for small reductions in long-term pain with local infiltration analgesia (three studies), ketamine infusion (one study), pregabalin (one study) and supported early discharge (one study) compared with no intervention. For electric muscle stimulation (two studies), anabolic steroids (one study) and walking training (one study) there was a suggestion of more clinically important benefit. No concerns relating to long-term adverse events were reported. For a range of treatments there was no evidence linking them with unfavourable pain outcomes. CONCLUSIONS:To prevent chronic pain after TKR, several perioperative interventions show benefits and merit further research. Good-quality studies assessing long-term pain after perioperative interventions are feasible and necessary to ensure that patients with osteoarthritis achieve good long-term outcomes after TKR. 10.1136/bmjopen-2018-028093
Central and peripheral analgesia mediated by the acetylcholinesterase-inhibitor neostigmine in the rat inflamed knee joint model. Buerkle H,Boschin M,Marcus M A,Brodner G,Wüsten R,Van Aken H Anesthesia and analgesia UNLABELLED:Intrinsic cholinergic inhibitory pathways present a key modulating system in pain perception. The use of intrathecal (i.t.) acetylcholinesterase-inhibitors, such as neostigmine, result in analgesia in both preclinical and clinical models. However, whether i.t. neostigmine suppresses tonic persistent pain or has peripheral sites of antinociceptive action has not been determined. Thus, we studied central (i.t.) and peripheral (intraarticular; i.a.) neostigmine in a rat inflamed knee joint model. Inhibition of thermal and mechanical hyperalgesia was assessed over 28 h using a modified Hargreaves box and von Frey hairs, respectively. I.t. neostigmine resulted in a dose-dependent thermal analgesia (50% of maximal effective dose [ED50] 0-4 h: 6.6 microg, 24-28 h: 9.4 microg) and mechanical analgesia (ED50 0-4 h: 3.5 microg, 24-28 h: 4.3 microg). I.t. atropine reversed analgesia by i.t. neostigmine. I.a. neostigmine also resulted in an i.a. atropine reversible dose-dependent increase of thermal analgesia, although it did not exceed 60% of a maximal possible analgesic effect with the largest applied dose (ED50 0-4 h: 76.2 microg, 24-28 h: 140.1 microg). Partial suppression of mechanical hyperalgesia was observed after i.a. neostigmine. We conclude that centrally administered neostigmine modulates thermal and mechanical antinociception in this animal model of inflammatory pain. These data suggest a peripheral site of muscarinic antinociception. IMPLICATIONS:This animal study shows that administration of the acetylcholinesterase-inhibitor neostigmine results in enhanced levels of the endogenous neurotransmitter acetylcholine, which seems to act as one of a group of analgesia-modulating compounds at central and peripheral sites in inflammatory pain. 10.1097/00000539-199805000-00023
Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis. The journal of pain UNLABELLED:Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain and a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present study, palpation of the ipsilateral hind limb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced expression of the early oncogene, FOS, in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways using a microinjection of lidocaine within the rostral ventromedial medulla induced conditioned place preference selectively in rats treated with the high dose of MIA. Conditioned place preference to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, intraperitoneally at -30 minutes). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID-resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that might guide drug discovery for treatment of advanced OA pain without the need for joint replacement. PERSPECTIVE:Difficulty in managing advanced OA pain often results in joint replacement therapy in these patients. Improved understanding of mechanisms driving NSAID-resistant ongoing OA pain might facilitate development of alternatives to joint replacement therapy. Our findings suggest that central sensitization and neuropathic features contribute to NSAID-resistant ongoing OA joint pain. 10.1016/j.jpain.2015.12.001
The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint. Seino Daisuke,Tokunaga Atsushi,Tachibana Toshiya,Yoshiya Shinichi,Dai Yi,Obata Koichi,Yamanaka Hiroki,Kobayashi Kimiko,Noguchi Koichi Pain Pain during inflammatory joint diseases is enhanced by the generation of hypersensitivity in nociceptive neurons in the peripheral nervous system. To explore the signaling mechanisms of mechanical hypersensitivity during joint inflammation, experimental arthritis was induced by injection of complete Freund's adjuvant (CFA) into the synovial cavity of rat knee joints. As a pain index, the struggle threshold of the knee extension angle was measured. In rats with arthritis, the phosphorylation of extracellular signal-regulated kinase (ERK), induced by passive joint movement, increased significantly in dorsal root ganglion (DRG) neurons innervating the knee joint compared to the naïve rats that received the same movement. The intrathecal injection of a MEK inhibitor, U0126, reduced the phosphorylation of ERK in DRG neurons and alleviated the struggle behavior elicited by the passive movement of the joint. In addition, the injection of U0126 into the joint also reduced the struggle behavior. These findings indicate that the ERK signaling is activated in both cell bodies in DRG neurons and peripheral nerve fibers and may be involved in the mechanical sensitivity of the inflamed joint. Furthermore, the phosphorylated ERK-positive neurons co-expressed the P2X3 receptor, and the injection of TNP-ATP, which antagonizes P2X receptors, into the inflamed joint reduced the phosphorylated ERK and the struggle behavior. Thus, it is suggested that the activation of the P2X3 receptor is involved in the phosphorylation of ERK in DRG neurons and the mechanical hypersensitivity of the inflamed knee joint. 10.1016/j.pain.2006.02.032
Inflammation-induced release of excitatory amino acids is prevented by spinal administration of a GABAA but not by a GABAB receptor antagonist in rats. Sluka K A,Willis W D,Westlund K N The Journal of pharmacology and experimental therapeutics After the injection of kaolin and carrageenan into the knee joint of rats, there was a decrease in paw withdrawal latency (PWL) to radiant heat ipsilaterally, which indicates hyperalgesia. This decrease was blocked by pretreatment of the spinal cord dorsal horn with the gamma-aminobutyric acid (GABAA) receptor antagonist, bicuculline but not with the GABAB receptor antagonist, CGP35348, administered by microdialysis. The inflammation-induced release of amino acids from the spinal dorsal horn occurred in two phases: 1) an early phase at the time of injection and 2) a late phase at 3.5 to 8 hr. The amino acids released in the late phase included aspartate (ASP), glutamate (GLU) and glutamine. During the PWL test, there was also the release of the inhibitory amino acids, serine and glycine, after the induction of arthritis. The increased release of excitatory amino acids at the time of injection was unaffected by pretreatment with either bicuculline or CGP35348. The release of amino acids during the late phase and during the PWL test was blocked by pretreatment with bicuculline but not CGP35348. The increase in joint circumference typical of this model did not occur with pretreatment with the GABAA receptor antagonist. The change in joint circumference was positively correlated with the late phase release of ASP and GLU. In bicuculline-treated arthritic animals in which joint inflammation was minimal, concentrations of ASP and GLU did not increase above base line.
Alternatives to Biologics in Management of Knee Osteoarthritis: A Systematic Review. Hassan Fadi,Murrell William D,Refalo Andrew,Maffulli Nicola Sports medicine and arthroscopy review BACKGROUND:Knee osteoarthritis (KOA) is a common condition encountered by physicians. KOA is addressed by a wide array of modalities including a number of nonbiological treatments. METHODS:PubMed, ISI Web of Science, and SPORTDiscus were searched for level 1 to 4 studies published from inception to August 2017. RESULTS:A total of 18 studies were evaluated and results demonstrated moderate supporting evidence for prolotherapy and limited evidence for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin. Evidence for local anesthetic agents was conflicting. CONCLUSION:There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin in improving pain and function. There is conflicting evidence for the use of local anesthetic agents in patients with KOA. 10.1097/JSA.0000000000000190
A pooled analysis of patient-specific factors and efficacy and tolerability of tapentadol extended release treatment for moderate to severe chronic pain. Etropolski Mila,Lange Bernd,Goldberg Jutta,Steup Achim,Rauschkolb Christine Journal of opioid management OBJECTIVE:To evaluate via retrospective analysis the efficacy and tolerability of tapentadol extended release (ER; 100-250 mg bid) based on patient-specific factors, including baseline pain intensity, prior opioid experience, gender, and body mass index (BMI). DESIGN:Data were pooled from three randomized, double-blind phase III studies of similar design that evaluated the efficacy and tolerability of tapentadol ER for the management of moderate to severe, chronic osteoarthritis knee pain (NCT00421928, NCT00486811) or low back pain (NCT00449176). SETTING:In the original trials, patients were recruited at primary, secondary, and tertiary care centers, institutional settings, and private practices in North America, Europe, Australia, and New Zealand. PATIENTS:Data were analyzed separately for groups of patients divided by baseline pain intensity, prior opioid experience, gender, and BMI. INTERVENTIONS:Patients received twice-daily placebo, tapentadol ER (100-250 mg), or oxycodone HCl controlled release (CR; 20-50 mg) for a 3-week titration and 12-week maintenance period. MAIN OUTCOME MEASURES:Changes from baseline in average pain intensity (11-point numerical rating scale) at week 12 of the maintenance period and for the overall maintenance period. RESULTS:Efficacy and tolerability were evaluated in 2,968 and 2,974 patients, respectively. The efficacy of tapentadol ER was shown in subpopulations divided by baseline pain intensity, prior opioid experience, gender, and BMI. Tapentadol ER was also shown to be well tolerated and associated with better gastrointestinal tolerability than oxycodone CR in the evaluated subpopulations (divided by prior opioid experience and gender). CONCLUSIONS:Results suggest that tapentadol ER (100-250 mg bid) provides similar pain relief and tolerability, regardless of baseline pain intensity, prior opioid experience, gender, or BMI. 10.5055/jom.2013.0177
Regulation of nitric oxide production by salicylates and tenidap in human OA-affected cartilage, rat chondrosarcomas and bovine chondrocytes. Attur M G,Patel R,DiCesare P E,Steiner G C,Abramson S B,Amin A R Osteoarthritis and cartilage OBJECTIVE:To examine the effects of non-steroidal anti-inflammatory drugs (NSAIDS) on nitric oxide (NO) and prostaglandin E2 (PGE2) production in chondrocytes from three different species. METHODS:We have estimated NO production by Griess method, and PGE2 by RIA from the supernatants of articular cartilage obtained from osteoarthritis joints (OA-affected cartilage), rat chondrosarcomas (in ex vivo conditions) and bovine chondrocytes (stimulated with cytokines + endotoxin in vitro conditions) in the presence or absence of aspirin, indomethacin, sodium salicylate, tenidap and glucocorticoids. RESULTS:NO, which was spontaneously released in ex vivo conditions by OA-affected cartilage and rat chondrosarcomas (maintained in vivo), was susceptible to inhibition by pharmacologically relevant concentrations of aspirin, sodium salicylate and tenidap, but not to concentrations of indomethacin or glucocorticoids that significantly inhibited PGE2 production under the same conditions. Similarly, the production of NO by bovine chondrocytes grown in monolayer cultures that had been stimulated with cytokines + endotoxins (in vitro) to release both NO and PGE2 (at 48-72 h post stimulation), were inhibited by aspirin, sodium salicylate and tenidap, but not by indomethacin or glucocorticoids at concentrations sufficient to PGE2 production. Inhibition of NO in the cytokines + endotoxin stimulated bovine chondrocytes (like the human OA-affected cartilage) augmented PGE2 production. CONCLUSION:These experiments demonstrate that NO production by chondrocytes across species show a similar profile of susceptibility to inhibition by selected anti-inflammatory drugs. The insensitivity of NO production to glucocorticoids is an important characteristics of these cells that merits further investigation. 10.1053/joca.1998.0120
Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain. Pain In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease. 10.1097/j.pain.0000000000000260
Effects of bushen huoxue decoction on nitric oxide (NO) in serum, articular cartilage and synovium in rabbits of knee osteoarthritis. Yang Pinglin,He Xijing,Yang Zhi,Liu Deyu,Li Haopeng,Wang Dong Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan UNLABELLED:Forty-eight New Zealand rabbits were divided into normal group (n=18), control group (n=18) and Chinese herbs treatment group (n=12) randomly. The rabbits in the normal group received sham-operation, and the OA model was established by Hulth's method. All the rabbits in the treatment group were given bushen huoxue decoction from the 6th week after the operation. At 6th, 8th and 12th week after the operation, the NO concentrations of the serum, joint cartilage and synovium were examined. RESULTS:Indicated that the NO concentrations of the serum, joint cartilage and synovium in the control group were all significantly higher than those in the normal group, with the joint cartilage more obvious (P<0.05). In the Chinese herbs treatment group the NO concentrations in all the parts obviously decreased as compared with the control group (P<0.05). It is suggested that bushen huoxue decoction decrease the levels of NO in the serum, synovium and joint cartilage in the OA rabbit.
Measuring physiotherapy performance in patients with osteoarthritis of the knee: a prospective study. Jamtvedt Gro,Dahm Kristin Thuve,Holm Inger,Flottorp Signe BMC health services research BACKGROUND:Patients with knee osteoarthritis [OA] are commonly treated by physiotherapists in primary care. Measuring physiotherapy performance is important before developing strategies to improve quality. The purpose of this study was to measure physiotherapy performance in patients with knee OA by comparing clinical practice to evidence from systematic reviews. METHODS:We developed a data-collection form and invited all private practitioners in Norway [n = 2798] to prospectively collect data on the management of one patient with knee OA through 12 treatment session. Actual practice was compared to findings from an overview of systematic reviews summarising the effect of physiotherapy interventions for knee OA. RESULTS:A total of 297 physiotherapists reported their management for patients with knee OA. Exercise was the most common treatment used, provided by 98% of the physiotherapists. There is evidence of high quality that exercise reduces pain and improves function in patients with knee OA. Thirty-five percent of physiotherapists used acupuncture, low-level laser therapy or transcutaneous electrical nerve stimulation. There is evidence of moderate quality that these treatments reduce pain in knee OA. Patient education, supported by moderate quality evidence for improving psychological outcomes, was provided by 68%. Physiotherapists used a median of four different treatment modalities for each patient. They offered many treatment modalities based on evidence of low quality or without evidence from systematic reviews, e.g. traction and mobilisation, massage and stretching. CONCLUSION:Exercise was used in almost all treatment sessions in the management of knee OA. This practice is desirable since it is supported by high quality evidence. Physiotherapists also provide several other treatment modalities based on evidence of moderate or low quality, or no evidence from systematic reviews. Ways to promote high quality evidence into physiotherapy practice should be identified and evaluated. 10.1186/1472-6963-8-145
Mori Folium water extract alleviates articular cartilage damages and inflammatory responses in monosodium iodoacetate‑induced osteoarthritis rats. Jeong Jin-Woo,Lee Hye Hyeon,Kim Jongsik,Choi Eun-Ok,Hwang-Bo Hyun,Kim Hong Jae,Kim Min Young,Ahn Kyu Im,Kim Gi-Young,Lee Ki Won,Kim Ki Young,Kim Sung Goo,Hong Su Hyun,Park Cheol,Cha Hee-Jae,Choi Yung Hyun Molecular medicine reports Mori folium, the leaf of Morus alba L. (Moraceae), has been widely used in traditional medicine for the treatment of various diseases. It has been recently reported that Mori folium possesses potential chondroprotective effects in interleukin (IL)‑1β‑stimulated human chondrocytes; however, its protective and therapeutic potential against osteoarthritis (OA) in an animal model remains unclear. In this study, as part of an ongoing screening program to evaluate the anti‑osteoarthritic potential of Mori folium, the protective effects of a water extract of Mori folium (MF) on cartilage degradation and inflammatory responses in a monosodium iodoacetate (MIA)‑induced OA rat model were evaluated. The results demonstrated that administration of MF had a tendency to attenuate the damage to articular cartilage induced by MIA, as determined by knee joint swelling and the histological grade of OA. The elevated levels of matrix metalloproteinases‑13 and two bio‑markers for the diagnosis and progression of OA, such as the cartilage oligomeric matrix protein and C‑telopeptide of type II collagen, were markedly ameliorated by MF administration in MIA‑induced OA rats. In addition, MF significantly suppressed the production of pro‑inflammatory cytokines, including IL‑1β, IL‑6 and tumor necrosis factor‑α. MF also effectively inhibited the expression of inducible nitric oxide (NO) synthase and cyclooxygenase‑2, thus inhibiting the release of NO and prostaglandin E2. Although further work is required to fully understand the critical role and clinical usefulness, these findings indicate that MF may be a potential therapeutic option for the treatment of OA. 10.3892/mmr.2017.7075
Proposed model of botulinum toxin-induced muscle weakness in the rabbit. Longino D,Frank Cy,Leonard T R,Vaz Marco A,Herzog Walter Journal of orthopaedic research : official publication of the Orthopaedic Research Society Osteoarthritic patients show only a weak association between radiographic signs of joint disease and joint pain and disability. Conversely, muscle weakness is one of the earliest and most common symptoms of patients with osteoarthritis (OA). However, while many experimental models of osteoarthritis include a component of muscular weakness, no model has isolated this factor satisfactorily. Therefore, the purpose of this study was to develop and validate an experimental animal model of muscle weakness for future use in the study of OA. Botulinum Type-A toxin (BTX-A) was uni-laterally injected into the quadriceps musculature of New Zealand white rabbits (3.5 units/kg). Isometric knee extensor torque at a range of knee angles and stimulation frequencies, and quadriceps muscle mass, were quantified for control animals, and at one- and six-months post-repeated injections, in both, the experimental and the contralateral hindlimb. Ground reaction forces were measured in all animals while hopping across two force platforms. Isometric knee extension torque and quadriceps muscle mass was systematically decreased in the experimental hindlimb. Vertical ground reaction forces in the push off phase of hopping were also decreased in the experimental compared to control hindlimbs. We conclude that BTX-A injection into the rabbit musculature creates functional and absolute muscle weakness in a reproducible manner. Therefore, this model may be used to systematically study the possible effects of muscle weakness on joint degeneration, either as an isolated intervention, or in combination with other interventions (anterior cruciate ligament transection, meniscectomy) known to create knee joint degeneration. 10.1016/j.orthres.2005.02.016.1100230625
Amelioration of Nicotine-Induced Osteoarthritis by Platelet-Derived Biomaterials Through Modulating IGF-1/AKT/IRS-1 Signaling Axis. Lo Wen-Cheng,Dubey Navneet Kumar,Tsai Feng-Chou,Lu Jui-Hua,Peng Bou-Yue,Chiang Pao-Chang,Singh Abhinay Kumar,Wu Chia-Yu,Cheng Hsin-Chung,Deng Win-Ping Cell transplantation Besides inhalation, a few studies have indicated that the uptake of nicotine through air or clothing may be a significant pathway of its exposure among passive smokers. Nicotine is well known to exert various physiological impacts, including stimulating sympathetic nervous system, causing vascular disturbances, and inducing cell death. Therefore, we aimed to establish whether exposure of nicotine could induce articular cartilage degeneration in a mouse model of osteoarthritis (OA). We specifically assessed dose-dependent effect of nicotine to mimic its accumulation. Further, during the studies, mice subcutaneously administered with nicotine was examined for OA-associated pathologic changes. We found that nicotine significantly suppressed chondrocytes and chondrogenic markers (Sox, Col II, and aggrecan). Nicotine-treated mice also showed altered knee joint ultrastructure with reduced Col II and proteoglycans. After corroborating nicotine-induced OA characteristics, we treated this pathologic condition through employing platelet-derived biomaterial (PDB)-based regenerative therapy. The PDB significantly suppressed OA-like pathophysiological characteristics by 4 weeks. The mechanistic insight underlying this therapy demonstrated that PDB significantly restored levels of insulin-like growth factor 1 (IGF-1) signaling pathway proteins, especially pIGF-1 R, pAKT, and IRS-1, regulating extracellular matrix synthesis by chondrocytes. Taken together, the PDB exerts regenerative and reparative activities in nicotine-mediated initiation and progression of OA, through modulating IGF-1/AKT/IRS-1 signaling axis. 10.1177/0963689720947348
Complex regional pain syndrome of the knee after conventional radiofrequency ablation of the genicular nerves treated successfully with dorsal root ganglion stimulation: A case report. Pain practice : the official journal of World Institute of Pain BACKGROUND:Radiofrequency (RF) treatment of the genicular nerves offers pain relief in patients suffering from chronic knee pain including persistent post-surgical knee pain (PPSP). We present the first case report of the development of complex regional pain syndrome (CRPS) in a chronic knee pain patient after an RF ablation of the genicular nerves that was successfully treated with dorsal root ganglion (DRG) stimulation. CASE PRESENTATION:The patient developed increased pain, sympathetic and dysmorphic changes of the index knee 10 weeks after RF treatment for PPSP. Diagnosis of CRPS type II was made using positive clinical findings and the Budapest diagnostic tool. Laboratory workup and PET-CT were negative. The patient was refractory to usual care and she was treated successfully with dorsal ganglion root stimulation. CONCLUSIONS:Complex regional pain syndrome is a possible complication of RF ablation of the genicular nerves in patients with chronic knee pain, and DRG stimulation may be a treatment option. Physicians should be aware of this complication, especially when patients have a medical history of CRPS. 10.1111/papr.13115