scholarly journals Melatonin Attenuates Pyroptosis Upon Spinal Nerve Ligation in Rats via the NF-κB/NLRP3 Inflammasome Signaling Pathway

2021 ◽  
Author(s):  
Yi-Hao Wang ◽  
Xiao Gao ◽  
Yu-Ru Tang ◽  
Nan-Nan Zhang ◽  
Zhao-Jun Liang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Potential Mechanism ◽  
Behavioral Experiments ◽  
Immune Mediated ◽  
Pain Models ◽  
Excessive Activation

Abstract Accumulated evidences have demonstrated causative links between neuropathic pain (NP) and immune-mediated inflammatory disorders. However, the role of inflammasome-induced pyroptosis in NP remains elusive. Melatonin possesses a well-documented analgesic action in various pain models. A rat model of spinal nerve ligation was established to explore the potential mechanism of melatonin in pyroptosis. The current study aimed to test our hypothesis that melatonin regulated pyroptosis to alleviate NP by inhibiting NF-κB/NLRP3-dependent signaling. Behavioral experiments revealed that SNL provoked severe allodynia which were suppressed by the administration of melatonin, caspase-1 inhibitor (VX-765) or NF-κB inhibitor (BAY 11-7085). SNL significantly up-regulated the inflammatory cytokines associated with the excessive activation of NLRP3 components and NF-κB signaling, as well as the marked pyroptosis activation which were partially inhibited by melatonin, VX-765 or BAY 11-7085. Collectively, Melatonin has potent analgesic and anti-inflammatory effects in SNL models through preventing pyroptosis via the NF-κB/NLRP3 inflammasome signaling pathway.

scholarly journals Characterization of New TRPM8 Modulators in Pain Perception

2019 ◽  
Vol 20 (22) ◽  
pp. 5544 ◽  
Author(s):  
Carmen De Caro ◽  
Claudia Cristiano ◽  
Carmen Avagliano ◽  
Alessia Bertamino ◽  
Carmine Ostacolo ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Pain Perception ◽  
Transient Receptor Potential ◽  
Pain Modulation ◽  
The Body ◽  
Sprague Dawley ◽  
Transient Receptor Potential Melastatin ◽  
Pain Models ◽  
Excessive Activation

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.

Role of bovine adrenal medulla 22 (BAM22) in the pathogenesis of neuropathic pain in rats with spinal nerve ligation

2012 ◽  
Vol 685 (1-3) ◽  
pp. 24-29 ◽  
Author(s):  
Tingjun Chen ◽  
Jianping Jiang ◽  
Hao Huang ◽  
Dongmei Wang ◽  
Yushan Liu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Adrenal Medulla ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Bovine Adrenal Medulla

Cyclooxygenase-1 in the Spinal Cord Is Altered after Peripheral Nerve Injury

2003 ◽  
Vol 99 (5) ◽  
pp. 1175-1179 ◽  
Author(s):  
Xiaoying Zhu ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Male Rats ◽  
Dependent Manner ◽  
Cyclooxygenase 1 ◽  
Cox 1

Background The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model. Methods Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord. Results COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level. Conclusion These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.

scholarly journals Role of Anoctamin-1 and Bestrophin-1 in Spinal Nerve Ligation-Induced Neuropathic Pain in Rats

2015 ◽  
Vol 11 ◽  
pp. s12990-015-0042 ◽  
Author(s):  
Jorge Baruch Pineda-Farias ◽  
Paulino Barragan-Iglesias ◽  
Emanuel Loeza-Alcocer ◽  
Jorge E Torres-Lopez ◽  
Héctor Isaac Rocha-Gonzalez ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Anoctamin 1

Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats

2015 ◽  
Vol 1622 ◽  
pp. 377-385 ◽  
Author(s):  
Sabino Hazael Avila-Rojas ◽  
Isabel Velázquez-Lagunas ◽  
Ana Belen Salinas-Abarca ◽  
Paulino Barragán-Iglesias ◽  
Jorge Baruch Pineda-Farias ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation

scholarly journals Exogenous stromal cell-derived factor-1 (SDF-1) suppresses the NLRP3 inflammasome and inhibits pyroptosis in synoviocytes from osteoarthritic joints via activation of the AMPK signaling pathway

2021 ◽  
Author(s):  
Shuya Wang ◽  
Ali Mobasheri ◽  
Yue Zhang ◽  
Yanli Wang ◽  
Tianqi Dai ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Stromal Cell ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Healthy Individuals ◽  
Mtor Signaling Pathway ◽  
Ampk Signaling ◽  
Stromal Cell Derived Factor

Abstract Objective NLRP3 inflammasome may play a key role in OA pathogenesis. Stromal cell-derived factor-1 (SDF-1) is a homeostatic CXC chemokine. Since the role of SDF-1 in OA has not been explored, this study aimed to examine the effect of SDF-1 on NLRP3 inflammasome and pyroptosis in synoviocytes from OA joints. Materials and methods Human synovium was obtained from OA patients for isolation of primary synoviocytes and a murine model of collagenase-induced OA was established for testing intra-articular injections of SDF-1. Immunoblotting assays were used to examine the effects and underlying mechanism of action of SDF-1 on NLRP3 inflammasome and synoviocyte pyroptosis in synoviocytes. Inhibitors of AMPK and PI3K–mTOR were utilized to investigate the key signaling pathways involved in SDF-1-mediated OA inflammasome formation and pyroptosis. Results Synoviocytes from OA joints exhibited significantly higher expression of NLRP3 inflammasome and biomarkers of synoviocyte pyroptosis relative to healthy individuals. This was confirmed in the collagenase-induced OA model, where OA synoviocytes had a significantly lower SDF-1 expression than healthy ones. SDF-1 treatment in synoviocytes of OA patients and collagenase-induced OA led to significant downregulation in the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Inhibition of the AMPK signaling pathway significantly suppressed the inhibitory effect of SDF-1 on NLRP3 inflammasome expression of OA synoviocytes. However, blocking the SDF-1-activated PI3K–mTOR signaling pathway could still suppress the expression of NLRP3 inflammasome and synoviocyte pyroptosis biomarkers. Conclusions SDF-1 ameliorates NLRP3 inflammasome and pyroptosis in OA synoviocytes through activation of the AMPK signaling pathway. Therefore, SDF-1 may be a novel therapeutic target for OA.

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