Neuroinflammation plays an important role in nerve-injury-induced neuropathic pain, but the explicit molecular mechanisms of neuroinflammation in neuropathic pain remain unclear. As one of the most critical inflammatory cytokines, interleukin-1β (IL-1β) has been regarded as broadly involved in the pathology of neuropathic pain. The inflammasome caspase-1 platform is one primary mechanism responsible for the maturation of IL-1β. Lipoxins, a type of endogenous anti-inflammatory lipid, have proved to be effective in relieving neuropathic pain behaviors. The present study was designed to examine whether the inflammasome caspase-1 IL-1β platform is involved in chronic constriction injury (CCI)-induced neuropathic pain and in lipoxin-induced analgesia. After rats were subjected to the CCI surgery, mature IL-1β was significantly increased in the ipsilateral spinal cord, and the inflammasome platform consisting of NALP1 (NAcht leucine-rich-repeat protein 1), caspase-1 and ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain) was also activated in spinal astrocytes and neurons, especially at the superficial laminae of the spinal dorsal horn; The aspirin-triggered-15-epi-lipoxin A4 (ATL), which shares the potent actions of the endogenous lipoxins, was administered to the CCI rats. Repeated intrathecal injection with ATL markedly attenuated the CCI-induced thermal hyperalgesia and significantly inhibited NALP1 inflammasome activation, caspase-1 cleavage, and IL-1β maturation. These results suggested that spinal NALP1 inflammasome was involved in the CCI-induced neuropathic pain and that the analgesic effect of ATL was associated with suppressing NALP1 inflammasome activation.
Keywords: ALX; ASC; ATL; Boc2; CARD; CCI; CSF; DMSO; ELISA; GAPDH; GFAP; HRP; IL; IgG; MMP; NALP; NALP1 inflammasome; NAcht leucine-rich-repeat protein; NeuN; Neuron-specific Nuclear Protein; PBS; PWL; SEM; TBST; apoptosis-associated speck-like protein containing a caspase-activating recruitment domain; aspirin-triggered-15-epi-lipoxin A4; butoxycarbonyl-Phe-Leu-Phe-Leu-Phe; caspase; caspase-activating recruitment domain; cerebrospinal fluid; chronic constriction injury; dimethyl sulfoxide; enzyme-linked immunosorbent assay; glial fibrillary acidic protein; glyceraldehyde 3-phosphate dehydrogenase; horseradish peroxidase; i.t.; immunoglobulin G; interleukin; intrathecal; lipoxin A4 receptor; metalloproteinase; neuropathic pain; paw withdrawal latency; phosphate-buffered solution; standard error; tris-buffered saline with tween.
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