Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada (K.H., S.G., M.W.S.); The University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada (K.H., S.G., M.W.S.); and The Department of Physiology, University of Toronto, Toronto, Ontario, Canada (S.G., M.W.S.).
Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada (K.H., S.G., M.W.S.); The University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada (K.H., S.G., M.W.S.); and The Department of Physiology, University of Toronto, Toronto, Ontario, Canada (S.G., M.W.S.)
J Pharmacol Exp Ther. 2020 Oct;375(1):202-209. doi: 10.1124/jpet.120.265017. Epub 2020 Feb 29.
For over two decades, purinergic signaling in microglia has persisted in the spotlight as a major pathomechanism of chronic pain. Of the many purinoreceptors, the P2X4R of the ionotropic family, has a well-described causal role underlying chronic neuropathic pain. This review will briefly examine microglial P2X4R signaling in the spinal cord as it relates to chronic pain through a historical lens, followed by a more in-depth examination of recent work, which has revealed major sex differences. We also discuss the generalizability of sex differences in microglial and P2X4R signaling in other pain conditions as well as in nonspinal regions. Finally, we speculate on remaining gaps in the literature as well as what can be done to address them with the ultimate goal of using our collective knowledge to treat chronic pain effectively and in both sexes. SIGNIFICANCE STATEMENT: Effective treatments are lacking for chronic pain sufferers, and this may be explained by the vast sex differences underlying chronic pain mechanisms. In this minireview, we focus on the roles of microglia and P2X4R in chronic pain, with specific attention to the circumstances under which these pathomechanisms differ between males and females. By delineating the ways in which pain occurs differently between the sexes, we can start developing successful therapies for all.
二十多年来，小胶质细胞中的嘌呤能信号转导一直是慢性疼痛的主要病理机制之一，备受关注。在众多嘌呤能受体中，离子型 P2X4R 受体在慢性神经病理性疼痛中起着明确的因果作用。本综述将从历史角度简要探讨脊髓中小胶质细胞 P2X4R 信号转导与慢性疼痛的关系，然后更深入地探讨最近的工作，这些工作揭示了主要的性别差异。我们还讨论了在其他疼痛状况以及非脊髓区域中小胶质细胞和 P2X4R 信号转导的性别差异的普遍性。最后，我们推测文献中仍然存在的差距，以及可以采取什么措施来解决这些差距，最终目标是利用我们的集体知识有效地治疗慢性疼痛，并且不论性别。
慢性疼痛患者缺乏有效的治疗方法，而这可能是由于慢性疼痛机制的基础存在巨大的性别差异。在这个小综述中，我们重点关注小胶质细胞和 P2X4R 在慢性疼痛中的作用，特别关注这些病理机制在男性和女性之间存在差异的情况。通过阐明疼痛在性别之间发生差异的方式，我们可以开始为所有人开发成功的治疗方法。
