脊髓GRK2/Epac1调控小胶质细胞表型转化在电针缓解慢性痛中的作用研究

项目名称： 脊髓GRK2/Epac1调控小胶质细胞表型转化在电针缓解慢性痛中的作用研究

项目编号： No.81473749

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 毛应启梁

作者单位： 复旦大学

项目金额： 73万元

中文摘要： 我们以往的工作表明，针刺可以有效缓解炎症痛、神经痛，但只能缓解早期小鼠皮肤癌痛，不能缓解晚期癌痛；针刺可以调节慢性痛时脊髓活化的小胶质细胞，下调致炎因子的表达。研究表明，癌痛与炎症痛、神经痛机理不全相同。慢性痛时，脊髓内G蛋白偶联受体激酶GRK2降低，使得下游Epac1活化，后者直接抑制了miR-124的作用，使得致炎型M1型小胶质细胞活化、抗炎型M2型小胶质细胞受抑制，释放炎症因子增加。脊髓GRK2/Epac1比例决定了慢性疼痛的转归。但是GRK2/Epac1介导的小胶质细胞活化分型以及miR-124在癌痛以及针刺镇痛中的作用至今仍不明确。我们的预实验表明，下调脊髓GRK2水平可以翻转电针的镇痛作用。本项目以小胶质细胞活化分型调节分子GRK2/Epac为切入点，比较脊髓小胶质细胞活化分型在针刺缓解炎症痛、神经痛与皮肤癌痛中的作用差异，来深入理解慢性痛以及针刺镇痛的内在机理。

中文关键词： G蛋白偶联受体激酶；微小RNA；小胶质细胞；电针镇痛；慢性痛

英文摘要： Our previous work shown that acupuncture effectively relieves inflammatory, neuropathic pain and cutaneous cancer pain at early stage but has no effect on cancer pain at late stage. Acupuncture exerts its analgesic effects through regulating spinal microglial activation and the proinflammatory cytokines expression. Researches had shown distinct mechanisms contribute to inflammatory, neuropathic pain and cancer pain. Recent reports shown that in chronic pain, decreased spinal G coupled receptor kinase GRK2 was observed. The low GRK2 subsequently facilitates the inhibiting effect of Epac1 on the regulatory element upstream of miR-124 gene, then activates proinflammatory (M1) microglia and deactivate antiinflammatory (M2) microglia. The decreased ratio of GRK2/Epac1 is a key neurobilogical mechanism underlying transition to chronic pain. However, whether GRK2/Epac1 and miR-124 are involved in acupuncture analgesia has not been reported. Our preliminary data showed i.t. injection of GRK2 antisense completely reverses acupuncture analgesia on pain. Hence, the present study is designed to observe the role of GRK2/Epac1 - miR-124 - M1/M2 microglia pathway in acupuncture analgesia on inflammatory, neuropathic pain and cutaneous cancer pain in mice. By comparing the different role of this signal pathway in acupuncture analgesia on different chronic pain, the study will help to further understand the mechanism underlie chronic pain and acupuncture analgesia.

英文关键词： G protein coupled receptor kinase;micro RNA;microglia;elecctroacupuncture analgesia;chronic pain