Abstract：
The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.
摘要：
许多疼痛状况的患病率通常因性别而异。除了这种数量上的区别，性二态性也可能是定性的，反映了男性和女性促进疼痛机制的差异。影响疼痛感知可能性的主要因素是激活伤害感受器的阈值。外周伤害感受器致敏已被证明在许多疼痛病症中是临床相关的。外周伤害感受器致敏是否可以以性别二态的方式发生，然而,尚未被广泛研究。为了解决这一基本知识差距，我们使用膜片钳电生理学来评估雄性或雌性啮齿动物背根神经节神经元的兴奋性，非人灵长类动物,以及暴露于推定的致敏剂后的人类。我们实验室以前的研究，和其他人,已经表明催乳素促进啮齿动物的女性选择性疼痛反应。与这些观察结果一致，背根神经节神经元来自女性，但不是男性,小鼠通过暴露于催乳素选择性致敏。在雌性猕猴的背根神经节神经元中也证实了催乳素的敏化作用。严重的,从女性身上恢复的神经元，但不是男性,人类供体也被催乳素选择性致敏。在睡眠和疼痛的研究过程中，我们意外地观察到食欲素拮抗剂可以使雄性动物的疼痛反应正常化。我们发现食欲素B对男性产生致敏作用，但不是女性，鼠标,猕猴,和人类背根神经节神经元。与功能反应一致，在雌性和雄性小鼠背根神经节中观察到催乳素受体和食欲素受体2表达增加，分别。对培养的人类感觉神经元和整个背根神经节的免疫组织化学询问也表明，女性催乳素受体表达增加，男性食欲素受体2表达增加。这些数据揭示了不同性别的伤害感受器致敏的功能性双重解离，它在物种中保守，可能与人类疼痛状况直接相关。据我们所知,这是人类感觉神经元功能性性二态性的首次证明。患者性别目前不是选择疼痛疗法的常见考虑因素。精准医学,基于患者性别,可通过选择性靶向促进女性或男性疼痛的机制来改善治疗结果.这些发现的其他含义是，疼痛治疗的临床试验设计应考虑男性或女性患者的比例。最后,可能需要通过性别亚组分析对部分过去失败的临床试验进行重新检查.
