激活延髓 ON 细胞 GPER-1 受体拮抗阿片镇痛介导术后疼痛慢性化

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.

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。

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患者术后生存质量。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。本课题聚焦研究ON细胞在术后慢性疼痛形成中的关键作用。通过4年可研究我们证实：1、GPER可作为RVM区ON细胞的标志分子。2、采用光遗传学的方法特异性激活GPER标记的ON细胞可降低小鼠机械和热痛阈值。3、约有16%的切口痛模型小鼠会发展为术后慢性疼痛状态。术后慢性疼痛小鼠RVM区GPER神经元激活的数目和GPER的表达均显著高于疼痛恢复小鼠。4、采用化学遗传学的方法特异性激活RVM区ON细胞可促进术后慢性疼痛的形成，抑制ON细胞的活性可避免术后慢性疼痛的发生。5、激活RVM区GPER受体可显著抑制吗啡的镇痛作用并促进吗啡耐受。术后慢性疼痛小鼠RVM中MOR的磷酸化水平显著高于疼痛恢复小鼠。化学遗传学特异性激活RVM区ON细胞可显著增强术后疼痛恢复小鼠MOR的磷酸化水平。激活RVM区ON细胞上的GPER受体可通过钙离子依赖的方式抑制MOR受体的功能。这些研究结果表明，术后慢性疼痛的发生与RVM区ON细胞的激活密切相关，激活的ON细胞可通过钙离子以来的方式抑制MOR受体的功能介导术后慢性疼痛的形成。. 本研究首次证明GPER可作为ON细胞的标记分子，为推动研究RVM在痛觉下行调制系统中的关键作用提供了便捷可靠的工具。此外，我们发现抑制ON细胞的活性可避免术后慢性疼痛的发生，为临床预防术后急性疼痛向慢性疼痛的转化和术后慢性疼痛的治疗提供了新的靶点和理论支撑。