糖尿病神经病理性疼痛鼠脑内核团异常自发放电及其与疼痛关系研究

Study on lesion of brain function is the hotspot of mechanism about diabetic neuropathic pain (DNP). Abnormal spontaneous discharge is an important form of nerve function lesion. If we confirm that multiple abnormal spontaneous discharge of brain nuclei participate in the development and maintain of the pain, the mechanisms of central pain in patients with DNP would be more clear and study of these nuclei lesions more deeper. Manganese ion, directly reflect the excitability of nerve cells, would be applied to select the spontaneous excitatory nuclei of brain in rats with DNP. These nuclei would be verified by electrophysiological methods in vivo, and the relationship among the nucleis identified by manganese ions enhanced MRI technology. Then the spontaneous discharge nucleus could be judged through combining the relationship among the nucleis with the synchronism of electrophysiological methods. Compared with basic self-generating electric activities, the different of the abnormal discharge would be observed and further verified by patch-clamp technique in vitro. Finally the effect of the abnormal discharge on pain would be assessed by praxiology tests, which would draw the conclusion that the abnormal discharge of multiple nuclei participated in the development and maintain of the pain. So the the mechanisms of pain would be perfect and new targets provided for further research.

脑功能病变研究已成为糖尿病神经病理性疼痛(diabetic neuropathic pain, DNP)机制研究的热点。异常自发放电是脑功能病变的重要形式。发现DNP脑内多处核团异常自发放电，了解其在疼痛发生和维持中的作用，有助于完善DNP中枢致痛机制；定位这些病变核团可为病理研究提供靶点。本研究拟应用可直接反映神经细胞兴奋性的功能磁共振技术筛选去脊髓传入的DNP鼠脑内兴奋性增强核团；通过活体电生理方法验证这些核团兴奋性增强并检测其放电同步性；应用磁共振神经通路成像技术明确这些核团间联系；结合核团间联系及其放电同步性初步判定其中的自发放电核团；对比正常大鼠自发电活动判定以上自发放电的异常性；应用膜片钳技术在离体情况下进一步验证这些异常自发放电；联合应用活体电生理检测与疼痛行为学检测评估这些核团放电对疼痛的影响。从而探讨DNP脑内多处核团异常自发放电参与疼痛发生及维持，为进一步研究提供支持。

本研究通过动脉给予锰离子鼠脑动态磁共振成像实验一定程度上完善了锰离子增强磁共振实验方法，构建了糖尿病大鼠模型，通过行为学实验选择糖尿病疼痛（DNP）大鼠，行锰离子增强磁共振成像检测DNP鼠脑内脑功能异常，发现了一部分自发增强的核团（包括感觉皮层、前扣带皮层、腹内侧前额叶皮层、嗅结节以及下橄榄核等），通过与糖尿病无痛大鼠行影像学分析及兴趣区分析，明确其中与疼痛相关的兴奋性增强核团（包括感觉皮层、腹内侧前额叶皮层、前扣带皮层、下橄榄核、梨状皮层、杏仁核及岛叶部分皮层），并发现一些与疼痛相关的功能抑制核团（包括初级运动皮层、次级运动皮层）。结合当前运动皮层电刺激已作为中枢神经痛的治疗方法，但尚未应用于周围神经痛治疗，提示运动皮层的功能干预也可能作为糖尿病周围神经痛的新的治疗方法之一，为下一步糖尿病疼痛的治疗研究提供了靶点。该项目剩余经费将用于进行DNP鼠脑运动皮层电刺激或无创的运动皮层经颅磁刺激实验验证该治疗方法。