CLC/CLF激活脊髓背角星形胶质细胞调控神经病理性痛发生的机制研究

神经病理性痛发病机制复杂，仍需深入研究。通过单细胞测序分析，我们新发现外周神经损伤可诱导心肌营养素细胞因子Clcf1在小鼠背根节（DRG）神经元中表达上调，其编码的CLC蛋白属于白介素IL-6家族。CLC需与类细胞因子CLF形成复合体发挥功能，但其对调控病理性痛是否有作用还未有研究。预实验结果显示小鼠鞘内给予CLC/CLF蛋白导致脊髓背角星形胶质细胞激活，还诱导机械性痛行为。在体RNA干扰抑制Clcf1在DRG神经元中的表达可显著缓解神经病理性痛行为。CLC/CLF还可增强脊髓II层神经元的自发性兴奋性突触后电流（sEPSC）的频率发放。上述结果提示CLC/CLF可通过激活星形胶质细胞和增强脊髓突触传递而调控神经病理性痛。综上，本申请将通过细胞分子生物学、行为药理学和电生理学等实验技术，阐明CLC/CLF调控神经病理性痛的作用及其细胞分子机制，为临床治疗提供新的药物靶点与重要科学依据。

The mechanism underlying neuropathic pain is complicated and still needs further study. Single-cell RNA sequencing of mouse DRG revealed that the cardiotrophin like cytokine factor 1 (Clcf1) expression was significantly up-regulated after peripheral nerve injury. The CLC encoded by Clcf1 belongs to IL-6 family and it needs to form a secreted complex with CLF. However, the function of CLC in neuropathic pain is not clear. Preliminary data showed that intrathecal injection of CLC/CLF could activate spinal astrocytes and induce the mechanical allodynia in the mice. Suppression of Clcf1 up-regulation by in vivo RNA interference could remarkably relieve the neuropathic pain. Meanwhile, CLC/CLF could increase the spontaneous EPSC (sEPSC) frequency of spinal layer II neurons. Based on the abovementioned data, we propose that CLC/CLF could regulate the neuropathic pain through activating the astrocytes and enhancing the synaptic transmission of dorsal spinal cord. In summary, we would clarify the role of CLC/CLF in regulating neuropathic pain and its molecular mechanism by cell biology, behavioral pharmacology, and electrophysiology method. Our work would provide the important scientific basis for finding new analgesic targets of the clinical treatment.