CCL2通过NMDAR介导的中枢敏化在臂丛神经根性撕脱伤引起的神经病理性痛产生和维持中的作用机制研究

Brachial plexus avulsion injury (BPA) is a peripheral nerve injury with high morbidity, hard treatment and poor prognosis and high prevalence of neuropathic pain(NPP), eventually leading to seriously dysfunction even disability in the upper limb. Communication between the activated glial cells and neurons in spinal dorsal horn of the injure sections are involved in the emergence and maintenance of pain and central sensitization. Emerging evidence revealed that CCL2 participates in glial cell activation and their connection with neurons, simultaneously,NMDAR may play a critical role in regulating CCL2-mediated information communication and pain transduction in glia cell-neuron and maintaining of hyperalgesia. We previously found that BPA injury induced overexpression of CCL2 and glial cell activation in rat spinal cord. This work is performed on the basis of BPA-NPP animal model and the upregulation of CCL2/CCR2 signaling, and to focus on the communication and interaction of glia-neuron in spinal cord concerning the effects of BPA injury on pain-related behavior, nerve electrophysiology and histopathology characteristics, distribution of CCL2-CCR2 and their roles of in regulating NMDAR, glia activation, finally the implication of JAK-STAT3 signal in the CCL2-induced NMDAR-mediated central sensitization and pain, which will provides a new strategy for the treatment of BPA injury caused neuropathic pain .

臂丛神经撕脱伤（BPA）是一种致残率高、治疗难度大、预后差的周围神经损伤，常并发神经病理性痛（NPP）而加重患肢功能障碍。受损节段脊髓背角活化的胶质细胞与神经元之间的信息交流参与中枢敏化及NP形成和维持。研究发现CCL2激活胶质细胞并参与胶质-神经元信息通讯同时NMDAR可能在CCL2引起的疼痛传导和痛敏维持中起作用，但CCL2在BPA诱发NPP作用机理不明。课题组发现BPA大鼠脊髓胶质细胞活化且CCL2高表达。本课题拟在BPA大鼠模型基础上，以CCL2/CCR2信号上调为立足点围绕胶质-神经元之间作用探讨BPA损伤对大鼠疼痛行为学、神经电生理学和组织病理学指标影响，CCL2/CCR2在受损脊髓节段的分布定位和对胶质细胞活化、NMDAR易化的调控作用，NMDAR在中枢敏化和疼痛维持中的作用以及JAK-STAT3信号在CCL2诱导NMDAR中的作用，为治疗BPA诱发的NPP提供新思路。

臂丛神经根性撕脱伤（Brachial Plexus Avulsion，BPA），又称为节前型损伤，是臂丛神经与脊髓交界区域的损伤，周围及中枢神经系统均有受累，除了存在患肢感觉及运动功能障碍外，伤后产生的神经病理性痛（Neuropathic Pain，NP）症状更是给患者带来了无尽的痛苦。NP也成为继感觉及运动功能障碍后BPA的第三大症状。现今临床对于NP的治疗仍处于探索期，对症治疗暂时降低患者的疼痛程度是主要的治疗手段，尚无预防及根治方法的原因是BPA诱发NP机制仍未阐明。本课题拟探讨CCL2及其受体在BPA诱发NP中的作用机制。利用课题组前期成功建立的BPA-NP大鼠模型为载体，将30只大鼠随机分为空白对照组、BPA-NP模型+生理盐水组、BPA-NP模型+CCR2抑制剂组、BPA-NP模型+JAK抑制剂组、BPA-NP模型+NR2B抑制剂组。分别检测各组大鼠C8-T1脊髓背角区域CCL2/CCR2免疫荧光表达及定量。同时通过Western Blot检测各组大鼠C8-T1脊髓背角区域CCL2、CCR2、NR2B蛋白表达量。分析各组数据的统计学差异。BPA-NP+生理盐水组大鼠脊髓背角CCL2/CCR2的荧光定量及蛋白表达量较BPA-NP+CCR2抑制剂干预组及空白对照组显著升高，差异具有统计学意义。本课题证实BPA-NP模型大鼠由于外伤因素导致脊髓背角神经胶质细胞内CCL2表达增高，进而与其受体CCR2结合通过激活下游JAK/STAT信号通路但并非唯一通路引起NMDA受体NR2B表达上调，增强中枢敏化作用导致NP的发生。CCL2-JAK/STAT-NMDA通路可能是BPA损伤诱发NP的机制之一。