Molecules in pain and sex: a developing story

Abstract

Microglia are dynamic immune cells with diverse roles in maintaining homeostasis of the central nervous system. Dysregulation of microglia has been critically implicated in the genesis of neuropathic pain. Peripheral nerve injury, a common cause of neuropathic pain, engages microglia-neuronal signalling which causes disinhibition and facilitated excitation of spinal nociceptive pathways. However, recent literature indicates that the role of microglia in neuropathic pain is sexually dimorphic, and that female pain processing appears to be independent of microglia, depending rather on T cells. Despite this sex difference, pain signalling in the spinal cord converges downstream of microglia, as NMDAR-mediated facilitated excitation in pain transmitting neurons is consistent between males and females. Determining whether pain signalling is sexually dimorphic in humans and, further, addressing the sex bias in pain research will increase the translational relevance of preclinical findings and advance our understanding of chronic pain in women.

Keywords: Microglia; Neuropathic Pain; Sex differences; Spinal Cord; T cells.

Fig. 1

Schematic showing the cellular and molecular pathway involved in neuropathic pain following peripheral nerve injury (top). The presence and/or relevance of the pathway in males and females is shown where elements of the pathway lie on the blue (male) and pink (female) lines. A solid line indicates evidence exists for involvement in that sex; a broken line indicates either absence of evidence or yet to be tested. Pathway components in red show known involvement in spinal changes leading to reduced inhibition, increased excitation and resultant increase in pain hypersensitivity. See text for further details