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.