Microglia, sex, and pain: even more twists and turns ahead?

Abstract

When IASP began 50 years ago, microglia were not on the radar of pain researchers. Indeed, interest only began to develop in earnest 25 years after IASP was established. Since then, there has been an explosion of information on microglia, particularly in animal models of chronic neuropathic pain. Microglia are regularly part of the conversation about neuropathic pain in animals and humans. The past 25 years has seen many unexpected twists and turns: microglia mediating neuropathic pain, profound mechanistic sex differences, helpful as well as hurtful microglia, and even microglia-independent neuropathic pain. Where will the story go in the next 50 years? Given the rapid growth in imaging of the panoply of cells, signaling molecules, and receptors in the central nervous system, it seems inevitable that the field will have determined whether microglia are intermediaries of chronic pain in humans and whether the mechanistic sex differences found in animal models exist in pain in humans. The principles of precision medicine may be applied to cell types and pathways increasingly identified in preclinical studies. However, application to humans will require advanced molecular diagnostics, not yet developed, for this approach to be successful. Alternatively, to develop safe and effective therapeutics, the field may take advantage of the points of convergence that have been revealed by studies on microglia and sex in pain. Time, and substantial efforts by passionate and talented pain researchers and clinicians, will tell. But what an exciting, and provocative journey it will be, undoubtedly full of novel twists and turns.