Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders. Baj Andreina,Bistoletti Michela,Bosi Annalisa,Moro Elisabetta,Giaroni Cristina,Crema Francesca Toxins Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases. 10.3390/toxins11080449
    A Neural Circuit from Thalamic Paraventricular Nucleus to Central Amygdala for the Facilitation of Neuropathic Pain. Liang Shao-Hua,Zhao Wen-Jun,Yin Jun-Bin,Chen Ying-Biao,Li Jia-Ni,Feng Ban,Lu Ya-Cheng,Wang Jian,Dong Yu-Lin,Li Yun-Qing The Journal of neuroscience : the official journal of the Society for Neuroscience As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVT-CeA-vlPAG circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions. Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVT-CeA-vlPAG pathway in a descending facilitatory mechanism underlying neuropathic pain. 10.1523/JNEUROSCI.2487-19.2020
    Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. Demir Ihsan Ekin,Tieftrunk Elke,Schorn Stephan,Saricaoglu Ömer Cemil,Pfitzinger Paulo L,Teller Steffen,Wang Kun,Waldbaur Christine,Kurkowski Magdalena U,Wörmann Sonja Maria,Shaw Victoria E,Kehl Timo,Laschinger Melanie,Costello Eithne,Algül Hana,Friess Helmut,Ceyhan Güralp O Gut OBJECTIVE:The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN:Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS:Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS:Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression. 10.1136/gutjnl-2015-309784
    The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor. Willert Robert Paul,Woolf Clifford J,Hobson Anthony Robert,Delaney Claire,Thompson David G,Aziz Qasim Gastroenterology BACKGROUND & AIMS:Visceral hypersensitivity is a common feature of functional gastrointestinal disorders. One speculated mechanism is an activity-dependent increase in spinal cord neuronal excitability (central sensitization), which is dependent on activation of the N-methyl-D-aspartate (NMDA) receptor. Our aims were to determine whether the development and maintenance of human visceral hypersensitivity is NMDA receptor mediated. METHODS:Healthy subjects were studied using a randomized, double-blind, placebo-controlled, crossover design. Pain thresholds to electrical stimulation were determined both in the proximal esophagus and in the foot (control) before and after a 30-minute distal esophageal infusion of 0.15 mol/L HCl acid. Ketamine (NMDA receptor antagonist) or saline (vehicle) was given intravenously either prior to or following acid infusion, and pain thresholds were measured for the following 120 minutes. Protocol 1: In 6 subjects, the effect of ketamine in the esophagus was assessed without acid infusion. Protocol 2: In 14 subjects, ketamine was given prior to esophageal acid. Protocol 3: In 12 subjects, ketamine was given after esophageal acid. RESULTS:Protocol 1: In the absence of esophageal acid, ketamine had no effect on either esophageal or foot pain thresholds (area-under-the-curve, [AUC] P = 0.36 esophagus, P = 0.34 foot, ANOVA) within 30 minutes of cessation of the infusion. Protocol 2: Acid-induced esophageal hypersensitivity was prevented by ketamine (AUC, P < 0.0001, ANOVA) without affecting foot pain thresholds (AUC, P = 0.06, ANOVA). Protocol 3: Ketamine delivered after acid reversed the induction of esophageal hypersensitivity induced by acid (AUC, P < 0.0001, ANOVA). CONCLUSIONS:The induction and maintenance of acid-induced esophageal hypersensitivity is prevented and reversed by ketamine. This finding strongly indicates that central sensitization is a mechanism of visceral hypersensitivity. 10.1053/j.gastro.2003.11.047
    Chemokines in chronic pain: cellular and molecular mechanisms and therapeutic potential. Jiang Bao-Chun,Liu Tong,Gao Yong-Jing Pharmacology & therapeutics Chronic pain resulting from nerve injury, tissue inflammation, and tumor invasion or treatment, is a major health problem impacting the quality of life and producing a significant economic and social burden. However, the current analgesic drugs including non-steroidal anti-inflammatory drugs and opioids are inadequate to relieve chronic pain due to the lack of efficacy or severe side-effects. Chemokines are a family of small secreted proteins that bind to G protein-coupled receptors to trigger intracellular signaling pathways and direct cell migration, proliferation, survival, and inflammation under homeostatic and pathological conditions. Accumulating evidence supports the important role of chemokines and chemokine receptors in the peripheral and central nervous system in mediating chronic pain via enhancing neuroinflammation. In this review, we focus on recent progress in understanding the comprehensive roles of chemokines and chemokine receptors in the generation and maintenance of different types of chronic pain, including neuropathic pain, inflammatory pain, cancer pain, and visceral pain. The current review also summarizes the upstream signaling of transcriptional and epigenetic regulation on the expression of chemokines and chemokine receptors as well as the downstream signaling of chemokine receptors underlying chronic pain. As chronic itch and chronic pain share some common mechanisms, we also discuss the emerging roles of chemokines and chemokine receptors in chronic itch. Targeting specific chemokines or chemokine receptors by siRNAs, blocking antibodies, or small-molecule antagonists may offer new therapeutic potential for the management of chronic pain. 10.1016/j.pharmthera.2020.107581
    Irritable bowel syndrome. Enck Paul,Aziz Qasim,Barbara Giovanni,Farmer Adam D,Fukudo Shin,Mayer Emeran A,Niesler Beate,Quigley Eamonn M M,Rajilić-Stojanović Mirjana,Schemann Michael,Schwille-Kiuntke Juliane,Simren Magnus,Zipfel Stephan,Spiller Robin C Nature reviews. Disease primers Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort, stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities. Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases, and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy. Although the underlying pathogenesis is far from understood, aetiological factors include increased epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and genetics, and altered brain-gut interactions. IBS considerably affects quality of life and imposes a profound burden on patients, physicians and the health-care system. The past decade has seen remarkable progress in our understanding of functional bowel disorders such as IBS that will be summarized in this Primer. 10.1038/nrdp.2016.14