Sex-Dependent Mechanisms of Chronic Pain: A Focus on Microglia and P2X4R

Abstract

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 first 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 non-spinal 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.

Single-cell RNA sequencing reveals time- and sex-specific responses of spinal cord microglia to peripheral nerve injury and links ApoE to neuropathic pain

“…but not in females 3,10,11 . To study the differences in responses of male and female microglia to peripheral nerve injury, we compared DEGs between two sexes.…”

“…Sexual dimorphism of microglia involvement in neuropathic pain has been extensively studied, revealing that microglia are necessary for the development of hypersensitivity in males but not in females 3,10,11 . To study the differences in responses of male and female microglia to peripheral nerve injury, we compared DEGs between two sexes.…”

“…Microglia play important roles in both the development and maintenance phases of neuropathic pain as inhibition or depletion of microglia 1-2 weeks or three months postnerve injury alleviate the hypersensitivity 5,8,9 . The role of microglia in neuropathic pain is known to be sex-dependent 10,11 . Microglia proliferation and morphological changes in response to peripheral nerve injury are present in both sexes; however, a functional role of microglia as critical drivers of neuropathic pain is observed in male but not in female animals [12][13][14][15][16] .…”

BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury

“…Recent findings have revealed that the contributing role of microglia in chronic pain is male biased [35,36]. In the spinal cord, activating Toll-like receptor 4, which is primarily expressed by microglia, by the agonist lipopolysaccharide, causes pain behavior in male but not female mice [37].…”

Parabrachial nucleus circuit governs neuropathic pain-like behavior

“…Sex dimorphism has been reported in some pain mechanisms [71][72][73] . In particular, a recent study reported that neuropathic pain is accompanied by sex-specific changes in the excitability and synaptic function of different subtypes of GABAergic neurons in prelimbic cortex 72 .…”