背根神经节神经元中Nogo-A 通过调控温度敏感型 TRP通道参与化疗药诱发的神经病理性疼痛

DRG神经元上的温度敏感型TRP通道参与化疗诱发的神经病理痛（CIPNP）发生。前期工作表明骨架调节蛋白Nogo-A是热敏感型通道TRPV1的调控分子。预实验显示在紫杉醇诱导的CIPNP大鼠模型的DRG中 Nogo-A和 TRPV1含量显著提高，而Nogo-A KO大鼠CIPNP程度显著降低。同时，冷觉感受器TRPM8在Nogo-A KO大鼠中显著增多，在CIPNP中显著下降。据此提出假说：DRG中Nogo-A通过调控温度敏感型TRP通道参与CIPNP。围绕该假说，拟首先确定Nogo-A促进CIPNP发生; 继而探讨Nogo-A是否通过影响囊泡运输降低TRPM8增强TRPV1功能，并通过减弱TRPM8对TRPV1功能的侧支抑制进一步增强TRPV1；最后探索Nogo-A拮抗剂与TRPM8激动剂联合抑制TRPV1发挥镇痛效应。本课题将揭示Nogo-A促进CIPNP发生并探讨机制，为相关镇痛药物开发提供新思路。

The Thermo-sensitive TRP channels in DRG play important roles in the Chemotherapy-Induced Peripheral Neuropathic Pain (CIPNP) and Nogo-A is a modulator of TRPV1. Our preliminary data showed that Nogo-A and TRPV1 were increased significantly in the DRG of rats with paclitaxel induced CIPNP, while in the Nogo-A KO rats the CIPNP was dramatically decreased. At the same time, TRPM8 was increased in the Nogo-A KO rat and decreased in the CIPNP. All these data indicate that Nogo-A plays a key role in the development of the CIPNP via modulating the thermo-sensitive TRP channels. This project will reveal that Nogo-A inhibites the TRPM8 and promotes the TRPV1 via influencing the vesicle transportation. Furthermore, the TRPM8 positive neurons inhibit the TRPV1 positive neurons by direct branches. Hence, the antagonist of Nogo-A could enhance the inhibition of TRPM8 to TRPV1 and could play as analgesics for treating the CIPNP. This project will reveal the involvement and mechanism of Nogo-A in CIPNP, and provide a new idea for the development of new analgesic drugs.