Department of Pharmacology-Physiology, Institut de pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada; Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l'Estrie - CHUS, Sherbrooke, Québec, Canada.
Department of Pharmacology-Physiology, Institut de pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada; Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l'Estrie - CHUS, Sherbrooke, Québec, Canada.
Neurosci Biobehav Rev. 2021 Jun;125:168-192. doi: 10.1016/j.neubiorev.2021.01.023. Epub 2021 Feb 12.
Chronic pain is a major global health issue that affects all populations regardless of sex, age, ethnicity/race, or country of origin, leading to persistent physical and emotional distress and to the loss of patients' autonomy and quality of life. Despite tremendous efforts in the elucidation of the mechanisms contributing to the pathogenesis of chronic pain, the identification of new potential pain targets, and the development of novel analgesics, the pharmacological treatment options available for pain management remain limited, and most novel pain medications have failed to achieve advanced clinical development, leaving many patients with unbearable and undermanaged pain. Sex-specific susceptibility to chronic pain conditions as well as sex differences in pain sensitivity, pain tolerance and analgesic efficacy are increasingly recognized in the literature and have thus prompted scientists to seek mechanistic explanations. Hence, recent findings have highlighted that the signaling mechanisms underlying pain hypersensitivity are sexually dimorphic, which sheds light on the importance of conducting preclinical and clinical pain research on both sexes and of developing sex-specific pain medications. This review thus focuses on the clinical and preclinical evidence supporting the existence of sex differences in pain neurobiology. Attention is drawn to the sexually dimorphic role of glial and immune cells, which are both recognized as key players in neuroglial maladaptive plasticity at the origin of the transition from acute pain to chronic pathological pain. Growing evidence notably attributes to microglial cells a pivotal role in the sexually dimorphic pain phenotype and in the sexually dimorphic analgesic efficacy of opioids. This review also summarizes the recent advances in understanding the pathobiology underpinning the development of pain hypersensitivity in both males and females in different types of pain conditions, with particular emphasis on the mechanistic signaling pathways driving sexually dimorphic pain responses.
慢性疼痛是一个全球性的重大健康问题，影响所有人群，无论其性别、年龄、族裔/种族或原籍国如何，导致持续的身体和情绪痛苦，并使患者丧失自主权和生活质量。尽管在阐明导致慢性疼痛发病机制的机制、确定新的潜在疼痛靶点以及开发新型镇痛药方面做出了巨大努力，但可用于疼痛管理的药理学治疗选择仍然有限，而且大多数新型止痛药都未能在临床开发中取得进展，使许多患者承受着无法忍受和管理不善的疼痛。文献中越来越多地认识到慢性疼痛状况的性别特异性易感性以及疼痛敏感性、疼痛耐受性和镇痛疗效的性别差异，并促使科学家寻求机制解释。因此，最近的发现强调了疼痛敏感性的信号机制存在性别二态性，这凸显了在两性中进行临床前和临床疼痛研究以及开发针对特定性别的疼痛药物的重要性。因此，本综述重点关注支持疼痛神经生物学存在性别差异的临床和临床前证据。提请注意胶质细胞和免疫细胞的性别二态作用，它们都被认为是神经胶质适应性可塑性起源于急性疼痛向慢性病理性疼痛转变的关键因素。越来越多的证据特别归因于小胶质细胞在性别二态性疼痛表型和阿片类药物的性别二态性镇痛疗效中起关键作用。本综述还总结了在理解不同类型疼痛状况下男性和女性疼痛敏感性发展的病理生物学方面的最新进展，特别强调了驱动性别二态性疼痛反应的机制信号通路。
