基于5-HT7R-cAMP-PKA通路探讨针刺对偏头痛模型镇痛的机制研究

Clinical studies have shown that acupuncture is effective in treating migraine, especially for the prevention of migraine by reduction in the number of migraine days and intensity of pain. We report that acupuncture can decrease pain-related behaviors and induce elevated 5-HT expression on neurons of trigeminovascular pain pathway. Recent studies indicate that acute, long-lasting sensitization of trigeminal nociceptive neurons occurs via distinct processes involving enhanced expression and function of 5-HT7 receptors. In particular, 5-HT via 5-HT7R-cAMP-PKA pathway involves the pain transmission and central sensitization. Furthermore, we propose plausible hypothetical mechanism that acupuncture can play an analgesic role of recurrent migraine model though modulation of 5-HT7 receptor alterations of trigeminovascular pain pathways, including the PAG, RVM and TCC, are for the maintenance of central sensitization. We focus on 5-HT7 receptor in the area of PAG/RVM/TCC and explore the correlation between 5-HT7 receptor and pain transmission in order to determine the function of 5-HT7R-cAMP-PKA in recurrent migraine model. Finally, our team will establish mechanism of acupuncture efficacy on recurrent migraine model in content of 5-HT7R-cAMP-PKA pathway.

预防性针刺在临床中已被证实能有效降低偏头痛发作天数和疼痛程度。课题组前期研究证实，针刺可以减少偏头痛大鼠自发及诱发痛行为，且可调节三叉神经血管痛觉系统中5-HT能神经元。目前研究发现，偏头痛病理状态下5-HT激活5-HT7R-cAMP-PKA通路，是参与疼痛信号传递的重要机制。据此我们提出“预防性针刺可以通过调控5-HT7R-cAMP-PKA通路参与偏头痛镇痛”的科学假说。拟采用疼痛行为学、高效液相色谱法及PepTag等技术，结合通路关键分子特异性拮抗剂，通过分析电针对下行易化/抑制系统的中脑导水管周围灰质(PAG)、延髓头端腹内侧区(RVM)、三叉神经颈髓复合体(TCC)区域5-HT7受体的变化，以及5-HT7R-cAMP-PKA通路的调控作用，探讨此通路在慢性偏头痛大鼠中对痛觉信号传递的作用，寻求针刺预防性干预慢性偏头痛大鼠的可能效应机制，为针刺预防性治疗偏头痛提供可能靶点和作用途径。

预防性针刺在临床中已被证实能有效降低偏头痛发作天数和疼痛程度。课题组前期研究证实，针刺可以减少偏头痛大鼠自发及诱发痛行为，且可调节三叉神经血管痛觉系统中5-HT能神经元。目前研究发现，偏头痛病理状态下5-HT激活5-HT7R-cAMP-PKA通路，是参与疼痛信号传递的重要机制。据此我们提出“预防性针刺可以通过调控5-HT7R-cAMP-PKA通路参与偏头痛镇痛”的科学假说。本研究应用疼痛行为学结合通路关键分子特异性拮抗剂等技术，通过分析针刺对内源性下行痛觉调制系统5-HT7受体的变化，以及5-HT7R-cAMP-PKA通路的调控作用，探讨此通路在慢性偏头痛大鼠中对痛觉信号传递的作用，寻求针刺预防性干预慢性偏头痛大鼠的可能效应机制，为针刺预防性治疗偏头痛提供可能靶点和作用途径。本研究结果证实针刺可缓解偏头痛大鼠中枢痛觉敏化状态下的皮肤异常疼痛，抑制TG区域及TCC核团c-Fos蛋白表达，即抑制神经元激活；进一步证实针刺可抑制偏头痛病理状态下疼痛信号传递相关的5-HT7R-cAMP-PKA通路关键蛋白表达，并采用5-HT7R拮抗剂SB269970和激动剂AS19分别模拟和拮抗针效，证实针刺通过特异性抑制5-HT7R改善偏头痛大鼠中枢痛觉敏化状态下的皮肤异常疼痛及TCC核团神经元激活。