围术期急性疼痛相对易于控制，而转为慢性疼痛就难以治愈并严重影响术后生存质量。因此，阐明急性疼痛慢性化机制是疼痛治疗的迫切需要。延髓RVM区是中枢下行调控疼痛的“闸门”，存在着一类可能易化疼痛的ON细胞。我们前期发现，雌激素GPER-1受体能特异性标记ON细胞且激活GPER-1显著抑制阿片的镇痛功能。本课题以术后慢性疼痛为研究模型，首先利用GPER-1-Cre小鼠特异性调控ON细胞，验证以往业界对激活ON细胞可促使疼痛慢性化的猜想；进一步分析激活GPER-1是否减弱了急性疼痛时内源性阿片对ON细胞的抑制，促使ON细胞持续兴奋而导致疼痛慢性化发生；最后，结合压力、抑郁及焦虑等“负向情绪”可能易化慢性疼痛发生的情况，研究围术期负向情绪是否通过增加RVM局部雌激素合成激活GPER-1，成为ON细胞持续兴奋的重要诱因。从而探索以“雌激素—GPER-1”为靶点，特异性抑制术后急性疼痛慢性化的治疗策略。

Acute postoperative pain is relatively easy to control, while it will be very difficult to cure and severely worse the daily life of patients after surgery when the chronification of postoperative pain happens, so we need to put more efforts to make the pain chronification mechanisms more clear to relief the pain. Rostral Ventromedial Medulla (RVM) is considered to be the gate control of pain transmission in spinal cord by descending modulation, in which there is a specific functional type of neuron named “ON cell” facilitating pain. According to our preliminary results, we found that the estrogen GPER-1 receptor could act as the marker of ON cell, and the opioid induced analgesia would be suppressed significantly after GPER-1 activation. For the further research in this proposal mainly focusing on the mechanisms of postoperative pain chronification, firstly, we will try to certify the exact role of ON cell activation on the pain modulation through the optogenetic modulation on the GPER-1-Cre mice. Secondly, it is important to clarify whether the facilitating effects of long lasting excited ON cell on pain chronification is mediated through the suppression of endogenous opioid analgesia by GPER-1 receptor activation. And finally, considering the perioperative negative emotion including pressure, depression and anxiety could promote the chronic pain, we will explore whether the estrogen in the RVM mediates this emotion and pain sensation interaction. We hope to provide more theoretical supports for the chronic postoperative pain treatments based on the “estrogen –GPER-1” pathway.