Involvement of the spinal NALP1 inflammasome in neuropathic pain and aspirin-triggered-15-epi-lipoxin A4 induced analgesia.
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.
Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai, China; Institute of Acupuncture Research, Institutes of Brain Science, Shanghai, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
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D000698:Analgesia / Q000379:methods; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D058847:Inflammasomes / Q000096:biosynthesis*; D007278:Injections, Spinal; D044045:Lipoxins / Q000008:administration & dosage*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D058847:Inflammasomes; D044045:Lipoxins; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; C040527:lipoxin A4; D001241:Aspirin
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