从杏仁核多巴胺系统介导的抗神经炎症通路探讨电针治疗慢性痛并发痛情绪的效应机制研究

Recently, accumulating evidences have demonstrated that efficient treatment of chronic pain should target both pain-modulating pathways and mood/affect networks. The excessive neuroinflammation in amygdala plays critical roles in the initiation and development of chronic pain and pain-related psychiatric disorders. Recent researches show that dopamine and its receptors are an important system bridging the nervous and immune systems, and play a key role in immune system regulation. Meanwhile, the dopamine system could be regulated by Electroacupuncture (EA). Electroacupuncture, evolving from traditional manual acupuncture, has good effects on chronic pain and pain-related psychiatric disorders. As the amygdala is a dopaminergic terminal region, and has the all types of dopamine receptors (Drd1-Drd5) widely expressed, we hypothesized that application of Electroacupuncture could inhibit the excessive neuroinflammation by activation of dopamine system in amygdale, which may result in antinociceptive, and markly improving the pain-related psychiatric disorders. Based on a neuropathic pain of mice model which is produced by chronic constriction injury (CCI) of the sciatic nerve, we observed the effects of Electroacupuncture on dopamine system regulation and neuroinflammation in the amygdala. Furthermore, the key downstream signaling pathway mediated by dopamine system to inhibit the neuroinflammation in the antinociceptive and improving the pain-related psychiatric disorders by Electroacupuncture was determined by behavior, morphology, neuropharmacology, proteomics, and so on. In this study, we attempted to clarify underlying mechanisms of Electroacupuncture-induced psycho-physiological regulation, which may provide rationale for the Electroacupuncture treatment on chronic pain management.

近期研究表明针对痛觉异常感受和痛情绪同时进行干预是有效治疗慢性痛的关键。中枢杏仁核过度的神经炎症反应是导致慢性痛和痛情绪产生的重要原因。新近研究表明多巴胺系统在免疫调节中发挥关键作用，且电针能调控多巴胺系统。鉴于杏仁核是多巴胺能神经纤维的终端部位，相关各型受体均广泛表达，我们推测电针可激活杏仁核多巴胺系统，抑制神经炎症，达到有效治疗慢性痛痛觉异常和痛情绪的作用。本项目拟采用神经病理性疼痛小鼠模型，观察电针对杏仁核多巴胺系统的调节和神经炎症的影响，综合运用行为学、形态学、神经药理学和蛋白组学等方法，离体和在体实验相结合，通过正/反向干预，从分子-细胞-行为的多层次系统研究，明确杏仁核多巴胺系统在电针治疗慢性痛并发痛情绪中的作用。并阐明多巴胺系统抑制神经炎症发挥治疗效应的下游关键信号通路。为揭示针刺疗法心身同调效应治疗慢性痛的作用机理有重要意义，为促进电针在慢性痛治疗中的临床应用提供理论依据。

慢性疼痛（Chronic Pain，CP）是一类发病率高、严重危害人类健康的疾病，是临床常见而有待于解决的关键问题。作为一种复杂的生理心理疾病，慢性疼痛包括了躯体痛觉异常感受和负面情绪（痛情绪）两个方面。电针（Electroacupuncture，EA）临床上广泛应用于各种病理性疼痛的治疗，而慢性疼痛是EA治疗的有效病种之一。既有的证据表明EA既能有效缓解慢性疼痛，又能同时改善慢性疼痛患者的焦虑和抑郁状态，达到综合治疗管理的目的，但是机制尚不十分清楚。中枢杏仁核过度的神经炎症反应是导致慢性痛和痛情绪产生的重要原因。新近研究表明多巴胺系统在免疫调节中发挥关键作用。因此，本课题探寻杏仁核多巴胺系统是否介导了EA治疗疼痛的多维度调控作用。本课题结果发现：（1）EA治疗可有效抑制坐骨神经慢性结扎性损伤（chronic constriction injury，CCI）诱导的慢性神经病理性疼痛大鼠的机械痛敏；（2）EA治疗可明显改善CCI模型大鼠的焦虑和抑郁样行为；（3）电针有效抑制CCI模型大鼠杏仁核的炎症反应水平；（4）CCI模型大鼠杏仁核多巴胺浓度降低，电针可上调杏仁核多巴胺的浓度；（5）同时电针治疗可调节多巴胺受体表达，特别是上调CCI模型大鼠杏仁核多巴胺受体1和多巴胺受体2的下调。（6）明确杏仁核多巴胺受体1和多巴胺受体2主要在神经元细胞表达；（7）通过体外实验结合转录组学研究，明确了DA、多巴胺受体1激动剂和多巴胺受体2激动剂作用神经元细胞后的转录组变化情况，发现多巴胺系统激活后下游重要的免疫-炎症调节涉及的重要通路。通过本研究，表明EA可以改善由慢性疼痛引起的机械性异常性疼痛和情绪障碍。杏仁核中DA系统的调节从而抑制局部神经炎症可能是EA发挥综合治疗效应的关键。本研究为揭示针刺疗法心身同调效应治疗慢性痛的作用机理有重要意义，为促进电针在慢性痛治疗中的临床应用提供理论依据。