Abstract
Accumulated evidence has 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. The current study aimed to test our hypothesis that melatonin regulated pyroptosis to alleviate NP by inhibiting NF-κB/NLRP3-dependent signaling. A rat model of spinal nerve ligation (SNL) was established to explore the potential association between melatonin and pyroptosis. Behavioral experiments revealed that SNL provoked severe allodynia which was suppressed by the administration of melatonin, a caspase-1 inhibitor (VX-765), or an 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 a marked pyroptosis activation. These effects were partially inhibited by melatonin, VX-765 or BAY 11-7085, and when melatonin and inhibitors were added together, the effect was enhanced. In conclusion, melatonin has potent analgesic and anti-inflammatory effects in SNL models through preventing pyroptosis via the NF-κB/NLRP3 inflammasome signaling pathway.
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The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
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No code was generated or used during the study.
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Acknowledgements
We sincerely thank Pro. Tao Sun (Shandong Provincial Hospital, Cheeloo College of Medicine) for his improving command of the manuscript.
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This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81972145).
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Conception and design: YL and FC; Administrative support: YL and FC; Provision of study materials or patients: YW, XG and YY; Collection and assembly of data: YW, XG and Y-RT; Data analysis and interpretation: YW, XG and MS; Manuscript writing: All authors; Final approval of manuscript: All authors.
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All the animal experiments of this study were approved by Qingdao University Animal Care and Use Committee.
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Wang, YH., Gao, X., Tang, YR. et al. The Role of NF-κB/NLRP3 Inflammasome Signaling Pathway in Attenuating Pyroptosis by Melatonin Upon Spinal Nerve Ligation Models. Neurochem Res 47, 335–346 (2022). https://doi.org/10.1007/s11064-021-03450-7
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DOI: https://doi.org/10.1007/s11064-021-03450-7