Morphine remains one of the most widely prescribed opioids for alleviation of persistent and/or severe pain; however, multiple preclinical and clinical studies report that morphine is less efficacious in females compared to males. Morphine primarily binds to the mu opioid receptor, a prototypical G-protein coupled receptor densely localized in the midbrain periaqueductal gray. Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray, and its descending projections to the rostral ventromedial medulla and spinal cord, as an essential descending inhibitory circuit mediating opioid-based analgesia. Remarkably, the majority of studies published over the following 30 years were conducted in males with the implicit assumption that the anatomical and physiological characteristics of this descending inhibitory circuit were comparable in females; not surprisingly, this is not the case. Several factors have since been identified as contributing to the dimorphic effects of opioids, including sex differences in the neuroanatomical and neurophysiological characteristics of the descending inhibitory circuit and its modulation by gonadal steroids. Recent data also implicate sex differences in opioid metabolism and neuroimmune signaling as additional contributing factors. Here we cohesively present these lines of evidence demonstrating a neural basis for sex differences in opioid modulation of pain, with a focus on the PAG as a sexually dimorphic core of descending opioid-induced inhibition and argue for the development of sex-specific pain therapeutics.

中文翻译：

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神经元和神经胶质因素导致阿片类药物疼痛调节的性别差异。


吗啡仍然是最广泛用于缓解持续性和/或严重疼痛的阿片类药物之一；然而，多项临床前和临床研究表明，与男性相比，吗啡对女性的疗效较差。吗啡主要与 mu 阿片受体结合，这是一种典型的 G 蛋白偶联受体，密集位于中脑导水管周围灰质。 20 世纪 60 年代进行的解剖学和生理学研究发现导水管周围灰质及其向延髓头端腹内侧和脊髓的下降投射是介导阿片类镇痛的重要下降抑制回路。值得注意的是，接下来 30 年发表的大多数研究都是在男性中进行的，隐含的假设是这种下行抑制回路的解剖学和生理学特征在女性中是相似的；毫不奇怪，事实并非如此。此后已确定有几个因素导致阿片类药物的二态性效应，包括下行抑制回路的神经解剖学和神经生理学特征的性别差异及其通过性腺类固醇的调节。最近的数据还表明阿片类药物代谢和神经免疫信号传导的性别差异是额外的影响因素。在这里，我们一致地提出这些证据，证明阿片类药物调节疼痛的性别差异的神经基础，重点是 PAG 作为阿片类药物诱导的下降抑制的性别二态性核心，并主张开发性别特异性疼痛治疗。