Li Q, Tian Y, Wang Z-F, Liu S-B, Mi W-L, Ma H-J, Wu G-C, Wang J, Yu J, Wang Y-Q
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.
Neuroscience. 2013 Dec 19;254:230-40. doi: 10.1016/j.neuroscience.2013.09.028. Epub 2013 Sep 25.
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.
神经炎症在神经损伤诱导的神经性疼痛中起重要作用，但神经炎症在神经性疼痛中的具体分子机制仍不清楚。作为最关键的炎症细胞因子之一，白细胞介素-1β（IL-1β）被广泛认为参与了神经性疼痛的病理过程。炎性小体半胱天冬酶-1平台是负责IL-1β成熟的主要机制之一。脂氧素是一种内源性抗炎脂质，已被证明可有效缓解神经性疼痛行为。本研究旨在探讨炎性小体半胱天冬酶-1 IL-1β平台是否参与慢性缩窄性损伤（CCI）诱导的神经性疼痛以及脂氧素诱导的镇痛作用。大鼠接受CCI手术后，同侧脊髓中成熟的IL-1β显著增加，由NALP1（含NAcht富含亮氨酸重复序列蛋白1）、半胱天冬酶-1和ASC（含半胱天冬酶激活募集结构域的凋亡相关斑点样蛋白）组成的炎性小体平台在脊髓星形胶质细胞和神经元中也被激活，尤其是在脊髓背角浅层；将具有内源性脂氧素强大作用的阿司匹林触发的15-表-脂氧素A4（ATL）给予CCI大鼠。反复鞘内注射ATL可显著减轻CCI诱导的热痛觉过敏，并显著抑制NALP1炎性小体激活、半胱天冬酶-1裂解和IL-1β成熟。这些结果表明，脊髓NALP1炎性小体参与了CCI诱导的神经性疼痛，且ATL的镇痛作用与抑制NALP1炎性小体激活有关。
