Menopausal women experience neuropathic pain 63% more frequently than men do, which may attribute to the estrogen withdrawal. However, the underlying mechanisms remain unclear. Here, the role of estrogen receptors (ERs) in ovariectomized (OVX) female mice following chronic constriction injury (CCI) was investigated. With 17β-estradiol (E2) supplemented, aggravated mechanical allodynia in OVX mice could be significantly alleviated, particularly after intra-anterior cingulate cortex (ACC) E2 delivery. Pharmacological interventions further demonstrated that the agonist of G-protein-coupled estrogen receptor 30 (GPR30), rather than ERα or ERβ in the ACC, exhibited the similar analgesic effect as E2, whereas antagonist of GPR30 exacerbated allodynia. Furthermore, OVX surgery reduced GPR30 expression in the ACC, which could be restored with estrogen supplementation. Selective downregulation of GPR30 in the ACC of naïve female mice induces mechanical allodynia, whereas GPR30 overexpression in the ACC remarkedly alleviated OVX-exacerbated allodynia. Collectively, estrogen withdrawal could downregulate the ACC GPR30 expression, resulting in exacerbated neuropathic pain. Our findings highlight the importance of GPR30 in the ACC in aggravated neuropathic pain during menopause, and offer a potential therapeutic candidate for neuropathic pain management in menopausal women.

中文翻译：

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前扣带皮层雌激素受体 GPR30 介导卵巢切除小鼠神经性疼痛加剧

更年期女性经历神经性疼痛的频率比男性高 63%，这可能是由于雌激素减少所致。然而，其根本机制仍不清楚。在此，研究了慢性缩窄性损伤（CCI）后雌激素受体（ER）在卵巢切除（OVX）雌性小鼠中的作用。补充 17β-雌二醇 (E2) 后，OVX 小鼠中加剧的机械异常性疼痛可得到显着缓解，特别是在前扣带皮层 (ACC) E2 递送后。药理干预进一步表明，G蛋白偶联雌激素受体30（GPR30）的激动剂，而不是ACC中的ERα或ERβ，表现出与E2相似的镇痛作用，而GPR30的拮抗剂则加剧了异常性疼痛。此外，OVX 手术降低了 ACC 中 GPR30 的表达，这种表达可以通过补充雌激素来恢复。雌性小鼠 ACC 中 GPR30 的选择性下调会诱发机械性异常性疼痛，而 ACC 中 GPR30 的过度表达则显着减轻 OVX 加剧的异常性疼痛。总的来说，雌激素戒断可能会下调 ACC GPR30 的表达，导致神经性疼痛加剧。我们的研究结果强调了 ACC 中 GPR30 在更年期期间神经病理性疼痛加重中的重要性，并为更年期女性的神经病理性疼痛管理提供了潜在的治疗候选者。