酪胺受体TAAR1参与三叉神经痛及其机制研究

Trigeminal neuralgia is a form of neuropathic pain characterized by severe lancinating pain in orofacial regions. However, up to now, the underlying mechanisms are still largely unclear. Our studies revealed that tyramine receptor TAAR1 were expressed in small-diameter trigeminal ganglion (TG) neurons. But in CFA mice, the expression of TAAR1 protein was significantly increased in TG neurons, which strongly suggested that TAAR1 might be involved in the pathophysiological process of trigeminal neuropathic pain. In this study, by using multiple animal behaviour tests, molecular immunohistochemistry, biological approaches and electrophysiological recording, we firstly confirmed the effects of TAAR1 on the trigeminal neuralgia, then we examined the endogenous expression of TAAR1 in TG and the co-localization of TAAR1 with nociceptors such as IB4, NF200 and CGRP. At last, we will further examine the effects of TAAR1 on neuronal excitability, ion channel currents, DNA methylation and relevant mechanisms in small-diamether TG neurons. Our studies will help to explore the relevant mechanisms of the trigger of trigeminal neuralgia. Meanwhile, our results will provide a new molecular target for the clinical treatment and the drugs development of trigeminal neuralgia.

三叉神经痛是一种以口面部严重刺痛为特征的神经病理性疼痛，迄今为止其发病机制仍未明确。我们的研究结果显示：酪胺受体TAAR1在小鼠小直径三叉神经节（TG）神经元中有表达。而在CFA模型小鼠中，其蛋白表达显著增高，提示TAAR1可能参与三叉神经痛的病理生理过程。本项目应用行为学、组织化学、分子生物学及电生理记录等实验方法，首先研究TAAR1对三叉神经痛小鼠的行为学影响；其次阐明TG内TAAR1的表达与共定位，如IB4, NF200 和 CGRP及TAAR1对TG神经元功能活动及相关蛋白表达的影响；最后揭示TAAR1对TG神经元兴奋性改变、离子通道电流变化、DNA甲基化的影响及其相关机制。研究结果不仅将揭示TAAR1参与三叉神经痛发生的相关机制，同时也为三叉神经痛的临床治疗和药物研发提供新的分子靶标。

三叉神经痛是一种以口面部严重刺痛为特征的神经病理性疼痛，迄今为止其发病机制仍未明确。本项目应用行为学、组织化学、分子生物学及电生理记录等实验方法，首先研究TAAR1对三叉神经痛小鼠的行为学影响；其次阐明TG内TAAR1的表达与共定位，如IB4, NF200 和 CGRP及TAAR1对TG神经元功能活动及相关蛋白表达的影响；最后揭示TAAR1对TG神经元兴奋性改变、离子通道电流变化及其相关机制。研究结果显示：酪胺受体TAAR1在小鼠小直径三叉神经节（TG）神经元中有表达，且在CFA模型小鼠中，其蛋白表达显著增高，提示TAAR1可能参与三叉神经痛的病理生理过程。应用行为学及全细胞膜片钳技术，检测TAAR1内源性配体酪胺对小鼠小直径TG神经元兴奋性的影响，显示TAAR1功能增强后TG神经元兴奋性增加，且其作用机制是通过激活PKCθ途径来影响A-型钾电流，从而引起TG神经元兴奋性增加，进而导致三叉神经痛。研究结果不仅阐明了TAAR1参与三叉神经痛发生的相关机制，同时也为三叉神经痛的临床治疗和药物研发提供新的分子靶标。发表SCI论文4篇；培养博士生1人，硕士生3人。