自噬对三叉神经节神经元五羟色胺受体3的调节及其在三叉神经痛中的作用

Trigeminal neuralgia is defined as sudden, severe, brief, stabbing recurrent episodes of pain within the distribution of one or more branches of the trigeminal nerve, which has a profound effect on quality of life. For the cause of Trigeminal neuralgia remains unclear, its treatment is still unsatisfactory. In previous research our group found that the level of 5-HT significant rised in the cerebrospinal fluid of the patients suffered by Trigeminal neuralgia, which demonstrated the improtant role of 5-HT in this disease. Further,based on the previous discovery that the serotonin receptor-3 is highly expressed in the peripheral parts of the trigeminal nerve by the introduction of serotonin, which increase the reaction to the mechanical stimulation, our further research found that serotonin may inhibit the autophagic degradation of 5-HTR3 through the PI3K/AKT/mTOR pathway which may be involved in the hyperalgesia of trigeminal nerve, but its mechanism is still unknown. This project intends to adopt the serial molecular biological techniques, such as laser scanning confocal microscope, transmission electron microscope, western blotting, immunofluorescence and animal behavior tests. By way of primary cultured trigeminal ganglion neurons and animal models we would clarify the relationship between 5-HT in inhibiting the autophagic degradation of 5-HTR3 that is invovled in hyperalgesia of trigeminal nerve, and then investigate the underlying mechanisms by which 5-HT regulates the autophagy. This project aims at improving the understanding of the etiology and attack mechanism, provide the new idea and therapeutic targets of the Trigeminal neuralgia.

三叉神经痛是面部三叉神经支配区域反复发作的剧烈疼痛，严重影响患者生活质量。由于其病因尚未完全阐明，治疗效果不甚理想。本课题组前期发现三叉神经痛患者脑脊液内5-HT水平升高，并据此在三叉神经痛动物模型中证明：在5-HT刺激下，三叉神经外周部分5-HTR3高表达，其明显增加疼痛反应，且此过程与自噬水平相关。进一步研究发现，5-HT可能通过PI3K／Akt／mTOR信号通路，抑制自噬，参与5-HTR3表达升高及疼痛反应，但其具体机制尚不清楚。本项目拟采用激光共聚焦、透射电镜、Western Blot、免疫荧光、动物行为学实验等方法，从三叉神经节原代神经元及三叉神经痛动物模型两个水平，明确5-HT对自噬的调节作用，及其与5-HTR3的表达量和三叉神经痛之间的关系。并探讨5-HT调节自噬及三叉神经痛的可能分子机制。将有助于完善对三叉神经痛发作机制的认识，为临床治疗三叉神经痛提供新的思路和靶点。