雌激素介导的NGF调节机制在子宫内膜异位症疼痛中的作用及中药干预研究

Endometriosis is a clinical common, frequently-occurring disease of gynaecology, pain is the most common clinical symptom, and seriously affects the quality of life of patients, pain relief is still the top priority of the current treatment . Endometriosis is a kind of estrogen dependent disease, in recent years, the study found that estrogen participated in pain by increasing the NGF, NGF plays in the induction of neuropeptides and at the same time increases the number of sensory neurons, including plays an important role in the occurrence of pain and hyperalgesia, at the same time there is evidence that the pain sensitization induced by NGF is mainly by activating TRPV1. From this we speculate that the NGF regulating mechanism mediated by estrogen may play an important role in the pain of EMs. Our previous study found that the therapy of tonifying kidney warming yang removing blood stasis can inhibit　the development of endometriosis by adjusting the disorder of reproductive hormones, inhibiting angiogenesis, reducing the state of adhesion. Also found that it was remarkable to ease dysmenorrhea and pelvic pain .This project intends to further study on the effect of the therapy on NGF regulating mechanism mediated by estrogen, to reveal the mechanism of Chinese Medicine treatment on pain. It is of great significance to interpret the mechanism of Chinese Medicine on pain, also enrich and perfect the TCM therapeutics of gynaecology.

子宫内膜异位症(EMs)是妇科常见疑难病，疼痛是其最常见的临床症状，严重影响患者的身心健康，缓解疼痛仍然是目前治疗EMs的首要任务。EMs是一种雌激素依赖性疾病，近年研究发现雌激素可以通过增加神经生长因子（NGF） 的生成参与疼痛的发生，NGF在诱导神经肽的同时增加感觉神经元的数量，在EMs疼痛及痛觉过敏的发生中起重要作用。有证据表明NGF诱导的痛觉增敏主要是通过激活瞬时受体电位辣椒素亚型1（TRPV1）起作用。由此推测雌激素介导的NGF调节机制可能在EMs疼痛的发生中发挥作用。前期研究发现补肾温阳化瘀疗法在缓解EMs患者痛经、改善盆腔疼痛等方面疗效显著，并且能够调节患者紊乱的生殖激素、抑制血管生成、改善黏附状态。补肾温阳化瘀疗法是否通过影响雌激素介导的NGF调节机制发挥“通则不痛”、缓解EMs疼痛的作用值得研究。这对于阐释中医药治疗痛证的作用机制，丰富和完善中医妇科治疗学具有重要意义。

子宫内膜异位症是妇科临床常见病，临床表现为痛经、慢性盆腔痛、性交痛、月经紊乱、不孕症、盆腔包块等。本病虽然是良性病变，但具有侵蚀、种植和易复发的特性，严重影响着患者的生活质量。因此探究内异症的发病机制并寻求用效的治疗方法成为研究的热点课题。子宫内膜异位症归属于中医妇科学“痛经”、“癥瘕”、“不孕”等范畴，其本质为血瘀。补肾温阳化瘀方由制附子、肉桂、川芎、川楝子、延胡索、桑寄生、党参、白术等药物组成，全方既能活血化瘀，使内异病灶瘀积得散；又能温补肾阳，促进瘀血的消散和吸收，共奏补肾温阳、化瘀止痛之功。本课题临床研究证实E2、NGF、BK、PGE2、PGF2α在内异症痛经患者血清中的水平升高并与痛经程度相关， ER、NGF、PGP9.5、BKB1R、TRPV1蛋白及基因在内异症痛经患者的在位、异位内膜的表达增强，并与内异症痛经患者VAS评分呈正相关关系，提示雌激素介导的NGF调节机制与内异症痛经的发生密切相关，NGF、BK、PGE2、PGF2α作为炎症因子及致痛物质，在内异症痛经的发生过程中存在相互促进、相互影响的关系，具有协同作用。动物实验证实补肾温阳化瘀方能够缩小子宫内膜异位症痛经模型小鼠异位灶体积，抑制内异症的发生发展；减少小鼠扭体次数，延长小鼠扭体潜伏期，缓解内异症痛经的发生。补肾阳化瘀中药能降低NGF、PGP9.5水平，抑制神经纤维再生，阻断疼痛传导信号，抑制痛经的发生。降低PGE2、PGF2α水平，缓解子宫平滑肌痉挛性收缩而抑制痛经的发生。降低BK/BKB1R的表达，降低BK的浓度，减少致痛物质的释放，阻断BKB1R介导的炎性反应。降低TRPV1的表达，阻断离子通道的激活，抑制痛觉增敏。降低E2/ER的水平阻断雌激素介导的一系列生物学反应从而缓解内异症痛经的发生。本课题证实雌激素介导的NGF调节机制是内异症发病的重要环节，补肾温阳化瘀中药可通过影响这一环节，使瘀血得散，阴寒得消，通则不痛，从而发挥治疗内异症的作用，为中医药治疗内异症提供了实验依据，丰富和完善了中医妇科治疗学。