Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking.
Nature neuroscience
Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls μ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the μ-opioid receptor against overstimulation.
10.1038/s41593-022-01135-0
Opioid tolerance and dependence in infants and children.
Anand K J,Arnold J H
Critical care medicine
OBJECTIVES:To review the definitions and scientific basis for opioid tolerance and dependence in neonates and older children; to assess objective methods for the clinical evaluation of opioid abstinence syndromes in this age group; and to suggest therapeutic strategies for the treatment of opioid abstinence in critically ill neonates and children. DATA SOURCES:The published literature on opioid tolerance and dependence in pediatric patients was reviewed. Data from current clinical practices, nursing procedures, and ongoing clinical research were evaluated. DATA SYNTHESIS:Currently proposed mechanisms of opioid tolerance and dependence are assessed, with particular relevance to the developing human central nervous system. The validity and clinical role of currently available objective methods for the assessment of opioid abstinence in neonates and older infants are defined. The efficacy of various pharmacologic and nonpharmacologic modalities for the treatment of opioid abstinence is evaluated and compared, and a therapeutic approach based on receptor mechanisms, clinical monitoring data, and pharmacologic efficacy is suggested. CONCLUSIONS:Important parallels for therapeutically-induced opioid tolerance and withdrawal may be drawn from the assessment and management of neonates born from opioid-addicted mothers. Opioid withdrawal can be prevented with appropriate weaning schedules, diagnosed by objective clinical methods, and treated by a variety of pharmacologic and non-pharmacologic means. Pharmacologic therapy includes the use of opioids, with adjuvant drugs such as diazepam, clonidine, or chlorpromazine. The pathophysiology and assessment of therapeutically induced opioid tolerance and withdrawal merit further research in critically ill pediatric patients.
10.1097/00003246-199402000-00027
Opioid tolerance and the emergence of new opioid receptor-coupled signaling.
Molecular neurobiology
Multiple cellular adaptations are elicited by chronic exposure to opioids. These include diminution of spare opioid receptors, decreased opioid receptor density, and G-protein content and coupling thereof. All imply that opioid tolefance is a manifestation of a loss of opioid function, i.e., desensitization. Recent observations challenge the exclusiveness of this formulation and indicate that opioid tolerance also results from qualitative changes in opioid signaling. In this article, Gintzler and Chakrabarti discuss the evidence that suggests that opioid tolerance results not only from impaired opioid receptor functionality, but also from altered consequences of coupling. Underlying the latter are fundamental changes in the nature of effectors that are coupled to the opioid receptor/G-protein signaling pathway. These molecular changes include the upregulation of adenylyl cyclase isoforms of the type II family as well as a substantial increase in their phosphorylation state. As a result, there is a shift in opioid receptor/G-protein signaling from predominantly Gialpha inhibitory to Gbetagamma stimulatory following chronic in vivo morphine exposure. These adaptations to chronic morphine indicate the plasticity of opioid-signal transduction mechanisms and the ability of chronic morphine to augment new signaling strategies.
10.1385/MN:21:1-2:021
[Development of opioid tolerance -- molecular mechanisms and clinical consequences].
Freye E,Latasch L
Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS
INTRODUCTION:One often identified effect of opioid administration is that of the development of tolerance to the analgesic effect. While it is generally agreed that tolerance to opioid analgesia does occur, it does not appear to be a limiting factor. Dose escalation in chronic pain therapy is considered to be predominantly a consequence of increasing pain, which is a result of increasing nociceptive input as the disease progresses. The underlying cause of tolerance to opioids, however, as commonly identified in the ICU can be identified as an adaptation process. When the opioid is given continuously several causes of adaptation can be identified, all of which can be traced back to the cellular and molecular level. RECEPTOR RELATED CHANGES INVOLVED IN TOLERANCE:Initial effects of opioid administration in most individuals are analgesia, sedation, nausea/vomiting, respiratory depression, pupillary constriction, constipation and euphoria or dysphoria. However, numerous studies and clinical experience suggest that tolerance to different opioid effects develop at different rates, which has been termed selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation and miosis. Such diversity suggest receptor-related differences in the speed of development of tolerance. In the ICU other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of tolerance of the latter. Such an effect very likely is due to a reduction in activity of the descending inhibitory nervous system. In addition, there is surmountable data suggesting that the higher the intrinsic activity of the opioid at only one receptor site, lesser receptors are needed in order to induce a potent analgesic effect. As a net result the incidence of tolerance is less likely to become clinically apparent when potent ligands such as fentanyl or sufentanil are administered. N-METHYL-D-ASPARTATE (NMDA) ACTIVATION, OPIOID RECEPTOR INTERNALIZATION AND DESENSITIZATION: An altered metabolism has little effect on the rate of development of tolerance. In chronic pain treatment with morphine, however, an increased ratio of the metabolite morphine-3-glucuronide, with antiopioid effects, to morphine-6-glucuronide is associated with staggering doses of the analgesic. Opioids which interact with micro - and/or kappa-binding sites, demonstrate an adaptation process called desensitization which is due to a reduced interaction with the internal second messenger system called G-protein. This is only a short-lived phenomenon following binding of the ligand. Another underlying mechanism of tolerance development is that of internalization of the opioid receptors. This short-lived phenomenon, termed endocytosis, results in lesser binding sites available for the mediation of analgesia. Another and more relevant mechanism of long-term opioid binding is that of subsequent protein kinase C (PKC), phospholipase C (PLC) translocation and activation of nitric oxide synthetase (NOS). All of this contributes to a N-methyl-D-aspartate (NMDA) receptor activation with ensuing antiopioid effect and tolerance. CLINICAL CONSEQUENCES FOLLOWING THE DEVELOPMENT OF TOLERANCE:Most likely genetic difference in opioid receptor synthesis and difference in their affinities for various ligands is the cause for the wide margin of dose variability in patients (genetic polymorphism). Once tolerance to the analgesic effect of the opioid is observed and in order to avoid unnecessary further development of tolerance, simultaneous administration of other receptor mediated analgesics is advocated. In the perioperative period strategies like the multimodal analgesic concept is fostered. It consists of the simultaneous administration of low-dose ketamine, co-administration of an alpha 2-agonist, and the administration of a selective COX-2 inhibitor (refecoxib, parecoxib) respectively. In chronic pain therapy combined administration with either dextromethorpharphane, or opioid rotation of a more potent ligand such as methadone, fentanyl TTS or oxycodone is suggested. Since conversion factors are not reliable in opioid rotation, it is best to start off with 50 % of the equivalent dose and rapidly titrate to the desired effect. With regard to tolerance development in the ICU, co-administration of an alpha 2-agonist (clonidine, dexmedetomidine), and daily intermittent cessation of benzodiazepine administration are advocated. Since continuous dosing of an opioid, commonly handled in the ICU setting is more likely to induce tolerance, intermittent administration is advocated. Taken together, there is an abundance of experimental data which suggests, that with every dose of an opioid several adaptive processes are being initiated. Due to genetic polymorphism such adaptation is seen clinically with striking individual different dosages, the degree and the time of onset of tolerance. Although tolerance development may result in staggering doses of an opioid, there is no reason to evade the use of such agents. On the contrary, the concept of multimodal analgesia consisting of the simultaneous use of analgesics with a different mode of action can counteract tolerance development.
10.1055/s-2003-36558
Locus-specific involvement of anti-opioid systems in morphine tolerance and dependence.
Ueda Hiroshi
Annals of the New York Academy of Sciences
Opioid tolerance and addiction could be discussed as two types of plasticity or counteradaptation, at the cellular level and through neuronal circuits. Cellular counteradaptation mechanisms include receptor desensitization through phosphorylation and endocytosis and through altered gene expression. The former mechanisms are related to the acute tolerance mechanisms, while the latter to chronic one. From current studies, it is known that various phosphorylation steps, such as protein kinase C (PKC) and G protein-coupled receptor (GPCR) kinase (GRK) regulate endocytosis. Of interest is that there are some differences in the physiological roles between opioid receptor endocytosis and other GPCR ones. Endocytosis of the opioid receptor is conceived as a recycling and resensitization step rather than the desensitization step. PKC phosphorylation inhibits endocytosis (PKC hypothesis). Therefore the PKC inhibitor attenuates acute analgesic tolerance. The agonist, which shows high-endocytosis stimulation, therefore makes less significant tolerance liability (RAVE hypothesis). Chronic tolerance is more likely related to the mechanisms through plastic modulation of neuronal circuits, where anti-opioidergic neurons are involved. The knockout mice lacking the receptors for anti-opioidergic nociceptin/orphanin FQ (N/OFQ) or glutamatergic neurons show weak or no morphine tolerance and dependence. As their gene expression or protein expression increases during chronic morphine treatments, we propose the hypothesis that the enhanced anti-opioid system may cause a counteradaptation to show tolerance and dependence. By a novel electroporation technique to deliver the receptor into the brain of knockout mice, we succeeded in determining the specific locus for the site of anti-opioid (through GluRepsilon1 or NR2A) action. All these results suggest that enhanced anti-opioid systems may contribute to the development of morphine tolerance and dependence, and their contributions could be brain locus specific.
10.1196/annals.1307.046
A molecular basis of analgesic tolerance to cannabinoids.
Tappe-Theodor Anke,Agarwal Nitin,Katona István,Rubino Tiziana,Martini Lene,Swiercz Jakub,Mackie Ken,Monyer Hannah,Parolaro Daniela,Whistler Jennifer,Kuner Thomas,Kuner Rohini
The Journal of neuroscience : the official journal of the Society for Neuroscience
Clinical usage of cannabinoids in chronic pain states is limited by their central side effects and the pharmacodynamic tolerance that sets in after repeated dosage. Analgesic tolerance to cannabinoids in vivo could be caused by agonist-induced downregulation and intracellular trafficking of cannabinoid receptors, but little is known about the molecular mechanisms involved. We show here that the type 1 cannabinoid receptor (CB1) interacts physically with G-protein-associated sorting protein 1 (GASP1), a protein that sorts receptors in lysosomal compartments destined for degradation. CB1-GASP1 interaction was observed to be required for agonist-induced downregulation of CB1 in spinal neurons ex vivo as well as in vivo. Importantly, uncoupling CB1 from GASP1 in mice in vivo abrogated tolerance toward cannabinoid-induced analgesia. These results suggest that GASP1 is a key regulator of the fate of CB1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids.
10.1523/JNEUROSCI.5648-06.2007
The other side of the opioid story: modulation of cell growth and survival signaling.
Chen Yulong L,Law Ping Yee,Loh Horace H
Current medicinal chemistry
Opioids have been used as pain control medications for thousands of years. Opioids are highly effective analgesics clinically available for controlling moderate and severe pain. Recent genetic knockout and knockin studies have definitively demonstrated that the analgesic effect is mediated through opioid receptors. In addition to their analgesic effect, opioids also have the potential to develop tolerance and physical dependence. Moreover, opioids can modulate cell proliferation and survival. Attempts to design better opioid drugs to eliminate or diminish these undesirable effects for clinical benefits have achieved limited success. In recent years, investigation of the effects of opioid-mediated cell proliferation and survival has been very active, resulting in many publications. However, the molecular targets of such non-analgesic effects are complex. Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the non-analgesic effects, which may be mediated through both opioid receptor signaling and other non-opioid receptor molecular entity-mediated signaling. This review tries to bring the attention of the medicinal chemistry community to new developments and advances in the research areas of opioid-mediated cell proliferation and survival. Further investigation of the molecular mechanism of these non-analgesic opioid effects may eventually yield useful information such as new drug targets, which may be explored to benefit for clinical treatments such as targeted cancer therapy, cancer pain management, regeneration of neurons, and recovery from drug addiction.
The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine.
Ozdemir Ercan,Bagcivan Ihsan,Durmus Nedim,Altun Ahmet,Gursoy Sinan
Canadian journal of physiology and pharmacology
Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180-210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), N(G)-nitro-L-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide-cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.
10.1139/y10-109
Heterologous regulation of agonist-independent μ-opioid receptor phosphorylation by protein kinase C.
Illing Susann,Mann Anika,Schulz Stefan
British journal of pharmacology
BACKGROUND AND PURPOSE:Homologous agonist-induced phosphorylation of the μ-opioid receptor (MOR) is initiated at the carboxyl-terminal S375, followed by phosphorylation of T370, T376 and T379. In HEK293 cells, this sequential and hierarchical multi-site phosphorylation is specifically mediated by G-protein coupled receptor kinases 2 and 3. In the present study, we provide evidence for a selective and dose-dependent phosphorylation of T370 after activation of PKC by phorbol esters. EXPERIMENTAL APPROACH:We used a combination of phospho site-specific antibodies, kinase inhibitors and siRNA knockdown screening to identify kinases that mediate agonist-independent phosphorylation of the MOR in HEK293 cells. In addition, we show with phospho site-specific antibodies were also used to study constitutive phosphorylation at S363 of MORs in mouse brain in vivo. KEY RESULTS:Activation of PKC by phorbol esters or heterologous activation of substance P receptors co-expressed with MORs in the same cell induced a selective and dose-dependent phosphorylation of T370 that specifically requires the PKCα isoform. Inhibition of PKC activity did not compromise homologous agonist-driven T370 phosphorylation. In addition, S363 was constitutively phosphorylated in both HEK293 cells and mouse brain in vivo. Constitutive S363 phosphorylation required ongoing PKC activity. When basal PKC activity was decreased, S363 was also a substrate for homologous agonist-stimulated phosphorylation. CONCLUSIONS AND IMPLICATIONS:Our results have disclosed novel mechanisms of heterologous regulation of MOR phosphorylation by PKC. These findings represent a useful starting point for definitive experiments elucidating the exact contribution of PKC-driven MOR phosphorylation to diminished MOR responsiveness in morphine tolerance and pathological pain.
10.1111/bph.12546
Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.
Mattioli Theresa Alexandra,Leduc-Pessah Heather,Skelhorne-Gross Graham,Nicol Chris J B,Milne Brian,Trang Tuan,Cahill Catherine M
PloS one
The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (-) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.
10.1371/journal.pone.0097361
Site and mechanism of morphine tolerance in the gastrointestinal tract.
Akbarali H I,Inkisar A,Dewey W L
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
Opioid-induced constipation is a major clinical problem. The effects of morphine, and other narcotics, on the gastrointestinal tract persist over long-term use thus limiting the clinical benefit of these excellent pain relievers. The effects of opioids in the gut, including morphine, are largely mediated by the μ-opioid receptors at the soma and nerve terminals of enteric neurons. Recent studies demonstrate that regional differences exist in both acute and chronic morphine along the gastrointestinal tract. While tolerance develops to the analgesic effects and upper gastrointestinal motility upon repeated morphine administration, tolerance does not develop in the colon with chronic opioids resulting in persistent constipation. Here, we review the mechanisms by which tolerance develops in the small but not the large intestine. The regional differences lie in the signaling and regulation of the μ-opioid receptor in the various segments of the gastrointestinal tract. The differential role of β-arrestin2 in tolerance development between central and enteric neurons defines the potential for therapeutic approaches in developing ligands with analgesic properties and minimal constipating effects.
10.1111/nmo.12443
Opioid receptor desensitization: mechanisms and its link to tolerance.
Allouche Stéphane,Noble Florence,Marie Nicolas
Frontiers in pharmacology
Opioid receptors (OR) are part of the class A of G-protein coupled receptors and the target of the opiates, the most powerful analgesic molecules used in clinic. During a protracted use, a tolerance to analgesic effect develops resulting in a reduction of the effectiveness. So understanding mechanisms of tolerance is a great challenge and may help to find new strategies to tackle this side effect. This review will summarize receptor-related mechanisms that could underlie tolerance especially receptor desensitization. We will focus on the latest data obtained on molecular mechanisms involved in opioid receptor desensitization: phosphorylation, receptor uncoupling, internalization, and post-endocytic fate of the receptor.
10.3389/fphar.2014.00280
Toll-like receptors and their role in persistent pain.
Lacagnina Michael J,Watkins Linda R,Grace Peter M
Pharmacology & therapeutics
One of the fundamental mechanisms whereby the innate immune system coordinates inflammatory signal transduction is through Toll-like receptors (TLRs), which function to protect and defend the host organism by initiating inflammatory signaling cascades in response to tissue damage or injury. TLRs are positioned at the neuroimmune interface, and accumulating evidence suggests that the inflammatory consequences of TLR activation on glia (including microglia and astrocytes), sensory neurons, and other cell types can influence nociceptive processing and lead to states of exaggerated and unresolved pain. In this review, we summarize our current understanding of how different TLRs and their accessory or adaptor molecules can contribute to the development and maintenance of persistent pain. The challenges and opportunities of targeting TLRs for new treatment strategies against chronic pain are discussed, including the therapeutic context of TLR-mediated signaling in opioid analgesia and chemotherapy-induced pain. Considering the prevalence of persistent pain and the insufficient efficacy and safety of current treatment options, a deeper understanding of Toll-like receptors holds the promise of novel therapies for managing pathological pain.
10.1016/j.pharmthera.2017.10.006
Tolerance to Morphine-Induced Inhibition of TTX-R Sodium Channels in Dorsal Root Ganglia Neurons Is Modulated by Gut-Derived Mediators.
iScience
In the clinical setting, analgesic tolerance is a primary driver of diminished pain control and opioid dose escalations. Integral to this process are primary afferent sensory neurons, the first-order components of nociceptive sensation. Here, we characterize the factors modulating morphine action and tolerance in mouse small diameter dorsal root ganglia (DRG) neurons. We demonstrate that acute morphine inactivates tetrodotoxin-resistant (TTX-R) Na channels in these cells. Chronic exposure resulted in tolerance to this effect, which was prevented by treatment with oral vancomycin. Using colonic supernatants, we further show that mediators in the gut microenvironment of mice with chronic morphine exposure can induce tolerance and hyperexcitability in naive DRG neurons. Tolerance (but not hyperexcitability) in this paradigm was mitigated by oral vancomycin treatment. These findings collectively suggest that gastrointestinal microbiota modulate the development of morphine tolerance (but not hyperexcitability) in nociceptive primary afferent neurons, through a mechanism involving TTX-R Na channels.
10.1016/j.isci.2018.03.003
Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming.
Araldi Dioneia,Bogen Oliver,Green Paul G,Levine Jon D
The Journal of neuroscience : the official journal of the Society for Neuroscience
In addition to analgesia, opioids produce opioid-induced hyperalgesia (OIH) and neuroplasticity characterized by prolongation of inflammatory-mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor Toll-like receptor 4 (TLR4) in OIH and priming induced by systemic low-dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of prostaglandin E hyperalgesia (priming) induced by LDM. In contrast, high-dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which was attenuated by TLR4 AS-ODN. Protein kinase C ε (PKCε) AS-ODN also prevented LDM-induced hyperalgesia and priming, whereas analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4 and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, whereas OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCε, HDM-induced analgesia, and priming are neither TLR4 nor PKCε dependent. OIH produced by LDM is mediated by both IB4 and peptidergic nociceptors, whereas priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4 and peptidergic nociceptors. Implications for the use of low-dose opioids combined with nonopioid analgesics and in the treatment of opioid use disorder are discussed. Opioid-induced hyperalgesia (OIH) and priming are common side effects of opioid agonists such as morphine, which acts at μ-opioid receptors. We demonstrate that OIH and priming induced by systemic low-dose morphine (LDM) share action at Toll-like receptor 4 (TLR4) and signaling via protein kinase C ε (PKCε) in common, whereas systemic high-dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCε dependent. OIH produced by systemic LDM is mediated by isolectin B4-positive (IB4) and peptidergic nociceptors, whereas priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4 and peptidergic nociceptors. Our findings may provide useful information for the use of low-dose opioids combined with nonopioid analgesics to treat pain and opioid use disorders.
10.1523/JNEUROSCI.0966-19.2019
Molecular mechanisms of opioid tolerance: From opioid receptors to inflammatory mediators (Review).
Zhou Jie,Ma Ruijie,Jin Ying,Fang Junfan,Du Junying,Shao Xiaomei,Liang Yi,Fang Jianqiao
Experimental and therapeutic medicine
Opioids are considered the most effective analgesics for the treatment of both acute and chronic pain. However, prolonged opioid use can induce a certain level of tolerance to its analgesic effects, leading to a reduction in its effectiveness, addiction and abuse. A better understanding of the mechanisms underlying opioid tolerance may provide insights into this phenomenon and aid in the development of novel methods to combat the side effects of opioid tolerance. The present review focused on two major contributors to tolerance, opioid receptors and inflammatory mediators. The molecular mechanisms involved in the desensitization of the opioid receptors were briefly described, including their phosphorylation, internalisation and recycling. Subsequently, the effects of Toll like receptor 4/NOD-like receptor family pyrin domain containing 3-mediated proinflammatory responses in opioid tolerance were discussed, aiming in supporting the identification of novel therapeutic targets.
10.3892/etm.2021.10437
Patching holes in the mechanism of opioid tolerance.
Trends in pharmacological sciences
Tolerance is a significant obstacle to use of opioids as safe pain relieving drugs, but the cellular processes that result in tolerance have remained elusive. A new study by Maza and colleagues identifies the protein Patched domain-containing 1 (PTCHD1) and its effects on cellular cholesterol as potential targets for preventing opioid tolerance.
10.1016/j.tips.2022.11.005
Addiction, physical dependence, and tolerance: precise definitions to help clinicians evaluate and treat chronic pain patients.
Heit Howard A
Journal of pain & palliative care pharmacotherapy
Pain is among the most common complaints for which people seek medical care; yet pain is also among the most undertreated patient complaints. Reasons for this include reluctance by clinicians to prescribe and support the use of opioids, often due to a fear of addiction. To address this issue, three major health professional organizations that deal with the treatment of pain and addiction, the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine, formed the Liaison Committee on Pain and Addiction (LCPA). The first mission of the LCPA was to formulate precise definitions of the terms addiction, physical dependence, and tolerance. This report explains these definitions and discusses how they apply to clinical practice.
10.1080/j354v17n01_03
Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice.
Schneider Jennifer P,Kirsh Kenneth L
Journal of opioid management
Treatment with opioid medications has grown over the past decades, but has been surrounded by some ongoing controversy and debate to whether it is causing more harm than good for patients. To this end, the field of pain management has suffered from a lack of clarity about some basic definitions on concepts such as tolerance and hyperalgesia. Some characterize these issues as inevitable parts of opioid therapy while other schools of thought look at these issues as relatively rare occurrences. Unfortunately, most of the rhetoric around these topics has occurred with very little in the realm of real world data. To this end, the authors have reviewed the charts of 197 patients treated by a pain specialist for at least 1 year to better illustrate whether notions of tolerance and hyperalgesia are common occurrences and, more importantly, whether they occur within any type of specified timeframe. A total of 197 patient charts were reviewed. The sample had an average age of 49.39 years (range = 19-87 years; standard deviation [SD] = 12.48) and comprised 66 men (33.5 percent) and 131 women (66.5 percent). The patients were seen in the pain practice for an average of 56.52 months (range = 12-155 months; SD = 31.26). On average, the patients maintained an average daily dose of 180 mg morphine equivalents for a period of 35.1 months (range = 3-101 months; SD = 21.3). Looking at the pattern of medication usage change over time, 34.5 percent experienced dose stabilization after the initial titration, 13.2 percent had early dose stabilization within one dose change, and an additional 14.7 percent actually had dose decreases after surgeries or other interventional procedures. Only 6.6 percent of the sample had to be discharged or weaned from controlled substances over time in the clinic. Thus, it appears that tolerance and hyperalgesia are not foregone conclusions when considering placing a patient on long-term opioid therapy.
10.5055/jom.2010.0036
Basics of Opioid Pharmacology.
Hansen John
South Dakota medicine : the journal of the South Dakota State Medical Association
The use of opioids in the treatment of chronic nonmalignant pain is neither endorsed nor proscribed by evidence-based medicine, except for the finding that opioids have certain risks. Also challenging for clinicians are consensus definitions for opioid pharmacology which are poorly chosen, changing, or euphemistic. This paper collects opioid consensus definitions for addiction, physical dependence, tolerance, and withdrawal, and offers practical discussion of the concepts they address. Addiction is a short-circuiting or overdrive of the mesocorticolimbic system of the brain. Physical dependence on opioids means that after chronic opioid dosing an abrupt cessation or marked dose decrease causes an opioid withdrawal syndrome. Physical dependence and addiction are unrelated neuroplastic phenomena which occur in different parts of the brain. Tolerance means a decreasing drug effect for a given dose over time. This applies to desired drug effects and to drug side-effects.
Role of β-arrestin-2 in short- and long-term opioid tolerance in the dorsal root ganglia.
European journal of pharmacology
G-protein-biased agonists with reduced β-arrestin-2 activation are being investigated as safer alternatives to clinically-used opioids. β-arrestin-2 has been implicated in the mechanism of opioid-induced antinociceptive tolerance. Opioid-induced analgesic tolerance is classically considered as centrally-mediated, but recent reports implicate nociceptive dorsal root ganglia neurons as critical mediators in this process. Here, we investigated the role of β-arrestin-2 in the mechanism of opioid tolerance in dorsal root ganglia nociceptive neurons using β-arrestin-2 knockout mice and the G-protein-biased μ-opioid receptor agonist, TRV130. Whole-cell current-clamp electrophysiology experiments revealed that 15-18-h overnight exposure to 10 μM morphine in vitro induced acute tolerance in β-arrestin-2 wild-type but not knockout neurons. Furthermore, in wild-type neurons circumventing β-arrestin-2 activation by overnight treatment with 200 nM TRV130 attenuated tolerance. Similarly, acute morphine tolerance in vivo in β-arrestin-2 knockout mice was prevented in the warm-water tail-withdrawal assay. Treatment with 30 mg/kg TRV130 s.c. also inhibited acute antinociceptive tolerance in vivo in wild-type mice. Alternately, in β-arrestin-2 knockout neurons tolerance induced by 7-day in vivo exposure to 50 mg morphine pellet was conserved. Likewise, β-arrestin-2 deletion did not mitigate in vivo antinociceptive tolerance induced by 7-day exposure to 25 mg or 50 mg morphine pellet in both female or male mice, respectively. Consequently, these results indicated that β-arrestin-2 mediates acute but not chronic opioid tolerance in dorsal root ganglia neurons and to antinociception in vivo. This suggests that opioid-induced antinociceptive tolerance may develop even in the absence of β-arrestin-2 activation, and thus significantly affect the clinical utility of biased agonists.
10.1016/j.ejphar.2021.174007
Synthesis of the Mechanisms of Opioid Tolerance: Do We Still Say NO?
Cellular and molecular neurobiology
The use of morphine as a first-line agent for moderate-to-severe pain is limited by the development of analgesic tolerance. Initially opioid receptor desensitization in response to repeated stimulation, thought to underpin the establishment of tolerance, was linked to a compensatory increase in adenylate cyclase responsiveness. The subsequent demonstration of cross-talk between N-methyl-D-aspartate (NMDA) glutamate receptors and opioid receptors led to the recognition of a role for nitric oxide (NO), wherein blockade of NO synthesis could prevent tolerance developing. Investigations of the link between NO levels and opioid receptor desensitization implicated a number of events including kinase recruitment and peroxynitrite-mediated protein regulation. Recent experimental advances and the identification of new cellular constituents have expanded the potential signaling candidates to include unexpected, intermediary compounds not previously linked to this process such as zinc, histidine triad nucleotide-binding protein 1 (HINT1), micro-ribonucleic acid (mi-RNA) and regulator of G protein signaling Z (RGSZ). A further complication is a lack of consistency in the protocols used to create tolerance, with some using acute methods measured in minutes to hours and others using days. There is also an emphasis on the cellular changes that are extant only after tolerance has been established. Although a review of the literature demonstrates a lack of spatio-temporal detail, there still appears to be a pivotal role for nitric oxide, as well as both intracellular and intercellular cross-talk. The use of more consistent approaches to verify these underlying mechanism(s) could provide an avenue for targeted drug development to rescue opioid efficacy.
10.1007/s10571-021-01065-8
Opioid tolerance and hyperalgesia.
Chang Grace,Chen Lucy,Mao Jianren
The Medical clinics of North America
Opioids have been successfully used for the management of acute and cancer-related pain. Concerns regarding side effects, tolerance, dependence, addiction, and hyperalgesia have limited the use of opioids for the management of chronic nonmalignant pain. This article will review updated information from both clinical and preclinical studies regarding opioid-induced hyperalgesia, tolerance, and dependence. The implications of these issues in clinical opioid therapy also will be discussed.
10.1016/j.mcna.2006.10.003
Mechanisms of opioid-induced tolerance and hyperalgesia.
DuPen Anna,Shen Danny,Ersek Mary
Pain management nursing : official journal of the American Society of Pain Management Nurses
Opioid tolerance and opioid-induced hyperalgesia are conditions that negatively affect pain management. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug's effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus. Complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying opioid tolerance. Pain facilitatory mechanisms in the central nervous system are known to contribute to opioid-induced hyperalgesia. Recent research indicates that there may be overlap in the two conditions. This article reviews known and hypothesized pathophysiologic mechanisms surrounding these phenomena and the clinical implications for pain management nurses.
10.1016/j.pmn.2007.02.004
Opioid-induced hyperalgesia and tolerance.
Bekhit Mary Hanna
American journal of therapeutics
We have all encountered the following postanesthesia care unit dilemma a myriad of times. As the attending covering the postanesthesia care unit, the anesthesiologist will be confronted not infrequently with the following clinical scenario: "He needed 500 μg fentanyl in the operating room for a toe amputation and has received 20 mg morphine, and he's still complaining of severe pain…. Do you think he may need more morphine?" Opiates do prevail as first-line therapy for moderate to severe surgical and chronic pain states. However, their use may actually confound the clinical picture postoperatively, because opiate exposure counterintuitively may actually trigger exaggerated pain sensation. When assessing a patient experiencing exaggerated postoperative or chronic pain, several questions should come to mind. First, is this patient experiencing tolerance or hyperalgesia induced by opiate therapy? Second, does the management differ for the two etiologies? Third, what underlying mechanisms, both at the neuroanatomic and molecular/chemical levels, underlie the two processes? Fourth, how does the recent literature on opiate-induced hyperalgesia influence previously accepted views of pre-emptive analgesia? Fifth, what treatment modalities exist for opiate-induced hyperalgesia? Most importantly, sixth, how can opiate-induced hyperalgesia be prevented? In this literature review, we aim to address these questions and to hopefully change the current perception and management of perioperative and chronic pain states with opiates.
10.1097/MJT.0b013e3181ed83a0
Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia.
Nature medicine
Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.
10.1038/nm.4262
Noncoding RNAs: Novel Targets for Opioid Tolerance.
Current neuropharmacology
As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.
10.2174/1570159X21666221129122932
Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.
Pharmacology research & perspectives
Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long-term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids' lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non-opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research.
10.1002/prp2.789
The effect of gut microbiome on tolerance to morphine mediated antinociception in mice.
Kang Minho,Mischel Ryan A,Bhave Sukhada,Komla Essie,Cho Alvin,Huang Charity,Dewey William L,Akbarali Hamid I
Scientific reports
There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration.
10.1038/srep42658
The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis.
Research square
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, . Fecal samples from morphine-treated mice had reduced levels of the phylum, , concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.
10.21203/rs.3.rs-3084467/v2
Opioid Modulation of the Gut-Brain Axis in Opioid-Associated Comorbidities.
Cold Spring Harbor perspectives in medicine
Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.
10.1101/cshperspect.a040485
Clinical Observation of the Effects of Oral Opioid on Inflammatory Cytokines and Gut Microbiota in Patients with Moderate to Severe Cancer Pain: A Retrospective Cohort Study.
Pain and therapy
INTRODUCTION:Recent studies have revealed that inflammation is a key factor in the causation of opioid analgesic tolerance. Opioids can induce a massive release of inflammatory cytokines and disruption of intestinal barrier function by activating Toll-like receptors 2/4 (TLR2/4), eventually resulting to sustained bacterial transmission and persistent systemic inflammation. However, most of the relevant analyses available were conducted at the level of animal experiments. It is necessary to explore the potential association between opioid tolerance and inflammatory cytokines and gut microbiota in patients with cancer pain. METHODS:We retrospectively analyzed cytokines, lymphocyte subsets and blood cells in 186 cancer patients to examine the effect of oral opioids on inflammatory cytokines in patients with moderate to severe cancer pain. The control group constituted tumor patients without cancer pain, while patients with moderate to severe cancer pain taking oral opioids made up the observation group. Fecal samples collected from 25 cancer patients were also analyzed for the composition and diversity of gut microbiota using 16S rRNA sequencing to explore the association between oral opioids and dynamic changes in gut microbiota. RESULTS:Patients with moderate to severe cancer pain taking oxycodone had significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ than those in the control group (p < 0.001). The difference in the relative abundance of Lactobacillus (p = 0.025), Anaerostipes (p = 0.034), Megamonas (p = 0.0080), Monoglobus (p = 0.0080), and the Rikenellaceae_RC9_gut_group (p = 0.022) between the opioid and control group was significant. CONCLUSION:Oral oxycodone can cause abnormal changes in cytokine levels and gut microbiota of patients with moderate to severe cancer pain, prompting chronic systemic inflammation. Analgesic tolerance induced by long-term oxycodone use could be closely related to the consistent upregulation of IL-6 and TNF-α levels.
10.1007/s40122-022-00386-w
On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance.
Fürst Susanna,Zádori Zoltán S,Zádor Ferenc,Király Kornél,Balogh Mihály,László Szilvia B,Hutka Barbara,Mohammadzadeh Amir,Calabrese Chiara,Galambos Anna Rita,Riba Pál,Romualdi Patrizia,Benyhe Sándor,Timár Júlia,Schmidhammer Helmut,Spetea Mariana,Al-Khrasani Mahmoud
Molecules (Basel, Switzerland)
There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.
10.3390/molecules25112473
Pain and Opioid-Induced Gut Microbial Dysbiosis.
Biomedicines
Opioid-induced dysbiosis (OID) is a specific condition describing the consequences of opioid use on the bacterial composition of the gut. Opioids have been shown to affect the epithelial barrier in the gut and modulate inflammatory pathways, possibly mediating opioid tolerance or opioid-induced hyperalgesia; in combination, these allow the invasion and proliferation of non-native bacterial colonies. There is also evidence that the gut-brain axis is linked to the emotional and cognitive aspects of the brain with intestinal function, which can be a factor that affects mental health. For example, , and are linked to Irritable Bowel Disease; and have associations with Parkinson's disease, and has increased prevalence in depression. However, changes to the gut microbiome can be therapeutically influenced with treatments such as faecal microbiota transplantation, targeted antibiotic therapy and probiotics. There is also evidence of emerging therapies to combat OID. This review has collated evidence that shows that there are correlations between OID and depression, Parkinson's Disease, infection, and more. Specifically, in pain management, targeting OID deserves specific investigations.
10.3390/biomedicines10081815
The Guts of the Opioid Crisis.
Physiology (Bethesda, Md.)
Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.
10.1152/physiol.00014.2021
Inflammatory mediators of opioid tolerance: Implications for dependency and addiction.
Eidson Lori N,Murphy Anne Z
Peptides
Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, most studies have examined the role of glia activation within the spinal cord. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This review attempts to summarize what is known regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance. These data, together, provide information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.
10.1016/j.peptides.2019.01.003
Opioid-free anesthesia opioid side effects: Tolerance and hyperalgesia.
Lavand'homme Patricia,Steyaert Arnaud
Best practice & research. Clinical anaesthesiology
Opioids are the most potent drugs used to control severe pain. However, neuroadaptation prevents opioids' ability to provide long-term analgesia and produces opposite effects, i.e., enhancement of existent pain and facilitation of chronic pain development. Neuroadaptation to opioids use results in the development of two interrelated phenomena: tolerance and "opioid-induced hyperalgesia" (OIH). Tolerance, a pharmacologic concept, and OIH, a clinical syndrome, have been mostly observed under experimental conditions in animals and in human volunteers. In contrast, their occurrence and relevance in clinical practice remain debated. In perioperative setting, intraoperative administration of high doses of opioids increases postoperative opioid requirements and worsens pain scores (acute tolerance or perioperative OIH). Further, preoperative chronic opioid intake and postoperative long-term use of opioid analgesics beyond the normal healing period have a negative effect on surgical outcome. Conversely, observations of improved patient's recovery after opioid-sparing anesthesia techniques stand as an indirect evidence that perioperative opioid administration deserves caution. To date, perioperative OIH has rarely been objectively assessed by psychophysics tests in patients. A direct relationship between the presence of perioperative OIH and patient outcome is missing and certainly deserves further studies.
10.1016/j.bpa.2017.05.003
Microglial inflammation modulates opioid analgesic tolerance.
Journal of neuroscience research
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
10.1002/jnr.25199
Chronic Morphine Induces IL-18 in Ileum Myenteric Plexus Neurons Through Mu-opioid Receptor Activation in Cholinergic and VIPergic Neurons.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
The gastrointestinal epithelium is critical for maintaining a symbiotic relationship with commensal microbiota. Chronic morphine exposure can compromise the gut epithelial barrier in mice and lead to dysbiosis. Recently, studies have implicated morphine-induced dysbiosis in the mechanism of antinociceptive tolerance and reward, suggesting the presence of a gut-brain axis in the pharmacological effects of morphine. However, the mechanism(s) underlying morphine-induced changes in the gut microbiome remains unclear. The pro-inflammatory cytokine, Interleukin-18 (IL-18), released by enteric neurons can modulate gut barrier function. Therefore, in the present study we investigated the effect of morphine on IL-18 expression in the mouse ileum. We observed that chronic morphine exposure in vivo induces IL-18 expression in the ileum myenteric plexus that is attenuated by naloxone. Given that mu-opioid receptors (MORs) are mainly expressed in enteric neurons, we also characterized morphine effects on the excitability of cholinergic (excitatory) and vasoactive intestinal peptide (VIP)-expressing (inhibitory) myenteric neurons. We found fundamental differences in the electrical properties of cholinergic and VIP neurons such that VIP neurons are more excitable than cholinergic neurons. Furthermore, MORs were primarily expressed in cholinergic neurons, although a subset of VIP neurons also expressed MORs and responded to morphine in electrophysiology experiments. In conclusion, these data show that morphine increases IL-18 in ileum myenteric plexus neurons via activation of MORs in a subset of cholinergic and VIP neurons. Thus, understanding the neurochemistry and electrophysiology of MOR-expressing enteric neurons can help to delineate mechanisms by which morphine perturbs the gut barrier.
10.1007/s11481-021-10050-3
The Emerging Perspective of Morphine Tolerance: MicroRNAs.
Zhang Teng J,Qiu Yong,Hua Zhen
Pain research & management
Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.
10.1155/2019/9432965
The gut-brain interaction in opioid tolerance.
Akbarali Hamid I,Dewey William L
Current opinion in pharmacology
The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.
10.1016/j.coph.2017.10.012
Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation.
Cahill Catherine M,Walwyn Wendy,Taylor Anna M W,Pradhan Amynah A A,Evans Christopher J
Trends in pharmacological sciences
Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs.
10.1016/j.tips.2016.08.002
Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia.
Colvin Lesley A,Bull Fiona,Hales Tim G
Lancet (London, England)
Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.
10.1016/S0140-6736(19)30430-1
Opioid-Induced Tolerance and Hyperalgesia.
Mercadante Sebastiano,Arcuri Edoardo,Santoni Angela
CNS drugs
Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.
10.1007/s40263-019-00660-0
Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement.
Koob George F
Biological psychiatry
Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system. However, they also engage the brain systems for stress and pain (somatic and emotional) while producing hyperalgesia and hyperkatifeia, which drive pronounced drug-seeking behavior via processes of negative reinforcement. Hyperkatifeia (derived from the Greek "katifeia" for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse. In animal models, repeated extended access to drugs or opioids results in negative emotion-like states, reflected by the elevation of reward thresholds, lower pain thresholds, anxiety-like behavior, and dysphoric-like responses. Such negative emotional states that drive negative reinforcement are hypothesized to derive from the within-system dysregulation of key neurochemical circuits that mediate incentive-salience and/or reward systems (dopamine, opioid peptides) in the ventral striatum and from the between-system recruitment of brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroimmune factors) in the extended amygdala. Hyperkatifeia can extend into protracted abstinence and interact with learning processes in the form of conditioned withdrawal to facilitate relapse to compulsive-like drug seeking. Compelling evidence indicates that plasticity in the brain pain emotional systems is triggered by acute excessive drug intake and becomes sensitized during the development of compulsive drug taking with repeated withdrawal. It then persists into protracted abstinence and contributes to the development and persistence of compulsive opioid-seeking behavior.
10.1016/j.biopsych.2019.05.023