基于NGF/ERK通路探讨益气散结汤缓解子宫腺肌症疼痛作用及机制

Dysmenorrhea as one of the main clinical symptoms and complained of adenomyosis (AM) patients, and seriously affected the AM patients reproductive health and life quality. Currently, surgery and drug therapy aim to AM pain symptoms has many problems. Chinese medicine has a unique on the understanding of the “pain”. Yiqi sanjie decoction as an experience prescriptions for the treatment on AM, clinical application can effectively alleviate the symptoms, animal model experiment confirmed that it can significantly improve AM hyperalgesia in mice and reduce the uterine nerve growth factor (NGF) mRNA expression level. Inflammatory reaction, nociceptive stimulus and neurogenic mechanism of three common mediated and promote AM pain occurs. Recent findings of high local model NGF expression may be associated with pain AM disorders related to inflammation and neuroendocrine, has become the key link in the AM pain research, and NGF mediated the Ras/ERK signaling pathway activation is closely related to abnormal pain by a variety of incentives.This project will be based on the previous research, the application of AM model by oral tamoxifen, further study the possible ways of Yiqi Sanjie decoction relieve AM hyperalgesia, and based on NGF/ERK pathway from the whole, the cellular and molecular level to explore the effect and mechanism of Yiqi Sanjie decoction alleviate pain.

痛经作为子宫腺肌病（AM）患者最主要的临床症状和主诉之一，严重影响了AM患者生殖健康和生活质量。当前针对AM疼痛症状的手术和药物治疗存在诸多问题，而中医在“疼痛”方面的认识有拥有独到之处。益气散结汤作为治疗AM有效经验方，临床运用可以有效缓解痛经症状，动物模型实验证实其可以显著改善AM小鼠痛觉过敏并降低子宫神经生长因子（NGF）mRNA表达水平。炎性反应、伤害性刺激及神经源性三大机制共同介导并促进AM疼痛的发生，最新研究发现局部NGF高表达可能与AM疼痛相关的炎症及神经内分泌的紊乱相关，已成为AM疼痛研究中的关键环节，而NGF介导的Ras/ERK信号通路活化与多种刺激诱发的异常疼痛密切相关。本项目将在前期研究基础之上，应用口服他莫昔芬法建立AM模型，进一步研究益气散结汤缓解AM痛觉过敏的可能途径，并基于NGF/ERK通路从整体、细胞和分子水平探讨益气散结汤抑制子宫腺肌病诱发疼痛效应机制。

痛经作为子宫腺肌症（AM）患者最主要的临床症状和主诉之一，严重影响了AM患者生殖健康和生活质量。当前针对AM疼痛症状的手术和药物治疗存在诸多问题，而中医在“疼痛”方面的认识有拥有独到之处。益气散结汤作为治疗AM有效经验方，临床运用可以有效缓解痛经症状，然而关于其抑制子宫腺肌症诱发疼痛效应的分子机制尚不清楚。本研究通过建立子宫腺肌病动物模型结合疼痛行为学实验从多个角度证实，益气散结汤可以显著改善AM小鼠痛觉过敏（包括冷、热、机械刺激等），同时可以显著改善子宫表面充血状态、减少子宫体表面结节数目及降低小鼠模型病理评分。进一步研究发现：益气散结汤可以有效降低子宫组织中刺激平滑肌收缩的一氧化氮（NO）、钙离子（Ca2+）、PGE2、PGF2α水平，并且可以通过调节促炎因子（IL-1β、IL-6、IL-8、TNF-α、RANTES、MCP-1）和抑炎因子（IL-10）水平来改善局部免疫微环境。机理研究发现益气散结汤可以通过调节靶器官（子宫体）和中枢系统（背根神经节，DRG）的神经生长因子（NGF-β）及其受体（p75NTR、TRKA）的表达来改善子宫腺肌症痛觉过敏。本项目研究结果将为进一步研究益气散结汤缓解AM痛觉过敏的可能途径，并基于NGF/ERK通路从整体、细胞和分子水平探讨益气散结汤抑制子宫腺肌症诱发疼痛效应机制打下坚实基础，同时也为益气散结汤临床应用治疗子宫腺肌病提供完整的理论依据。