NO/NOS为靶的褪黑素多位点调控口颌面部炎性疼痛昼夜变化的外周机制

Nocturnal suffering of the inflammatory pain troubles patients and clinician a lot, but the underlying mechanism is still unknown. Researches indicated that melatonin (MT) was implicated in the inflammatory pain processing by exerting up- or down regulatory effect on NO/NOS system on multiple sites. Moreover, different level of MT may lead to different acting sites. Our research team found that, NO/NOS positive neurons in the trigeminal ganglia (TG) played a role in the modulation of orofacial inflammatory pain.( Brain Res. Rev,59:324-333, IF:7.39）. Whether the rhythmic secretion of MT, which is higher at nocturnal hours, causes diurnal variations in inflammatory pain by acting on different sites in the NO/NOS system? This study will further explore the effect of different level of MT on the inflammatory pain and diurnal changes of NO/NOS system in the TG, based on which, siRNA will be used to block different modulatory sites of MT on NO/NOS system respectively to study the relative change on nociceptive behavior, NO/NOS system and electrophysiological of the TG neurons. We attempte to lay the foundation for researches on MT modulating inflammatory pain and NO/NOS system, provide new target for developing new analgesic, meanwhile offer new ideas for releasing clinical inflammatory pain at nocturnal hours.

炎性疼痛的夜间痛严重困扰着患者和临床工作者，但机制不明。研究表明褪黑素（MT）参与调控炎性疼痛，可多位点抑制NO/NOS系统，也有促进该系统的位点；研究还表明，不同浓度MT可作用于不同位点。本课题组研究发现，三叉神经节（TG）神经元NO/NOS参与调控口颌面部炎性疼痛（Brain Res. Rev,59:324-333, IF:7.39）。那么，是否MT昼低夜高的分泌差异，使其作用于不同的TG神经元NO/NOS位点，引起口颌面部炎性疼痛昼夜变化呢？本项目在体内外进一步研究不同浓度MT对口颌面部炎性疼痛和TG神经元NO/NOS昼夜变化基础上，应用siRNA技术分别阻断MT调控NO/NOS系统的不同作用位点，研究其对疼痛行为、TG神经元NO/NOS系统和电生理的影响，为MT调控炎性疼痛机制及NO/NOS作用位点的研究奠定基础，为开发镇痛新药提供新靶点，并为临床减缓炎性疼痛的夜间痛提供新思路。

炎性疼痛的夜间痛严重困扰着患者，但机制不明。围绕MT是否通过调节TG神经元NO/NOS系统进而调节痛觉信号的传递，本项目深入探讨了MT调控口颌面炎性疼痛昼夜变化机制，最主要的研究进展是明确了MT1R在正常大鼠三叉神经节（Trigeminal ganglion, TG）内大量表达并与NADPH-d共表达。MT可调控TG神经元NO/NOS系统昼夜变化差异，且这种差异被证明是引起口颌面炎性疼痛昼夜变化的机制。研究还发现，当归芍药散新配方可有效缓解大鼠颌面炎性疼痛，有望开发镇痛新药，并为临床减缓炎性疼痛的夜间痛提供新思路,为MT调控炎性疼痛夜间痛机制研究奠定基础，本项目各项研究内容进展顺利，并已取得多项成果。从 2015~2018年在 life sciences，journal of molecular histology等杂志发表论文13篇，其中Sci收录8篇，国内外学术交流9次。培养硕士研究生4名，博士研究生1名。