Investigating the Cell-specific Mechanisms That Drive Sex Differences During Neuropathic Pain Development

Chronic pain patients often suffer from a decline in quality of life due to a lack of efficacious long- term therapeutics. Moreover, the prevalence of chronic pain conditions is on the rise, with an average increase of nearly 10 percent in patients per decade. This, coupled with the devastating impact of the opioid crisis, highlights the need for novel pain therapeutics. An extensive literature has placed microglia, the resident immune cells of the central nervous system, at the forefront of male-specific mechanisms that mediate chronic pain plasticity. Recently, efforts have been made to design studies aimed at dissecting female specific mechanisms in pain plasticity. Evidence suggests that immune-related components of nociceptors are heavily dysregulated following insult and are more directly responsible for changes in female-specific sensitization. Despite advances in the field of pain neurobiology, there remains a clear disconnect between the cellular mechanisms that underlie maladaptive chronic pain in males and females. Moreover, a lack of studies directed towards interventions during early neuropathic pain development make it difficult to assess how functional changes in cellular phenotypes following injury can be manipulated to prevent maladaptive pain plasticity from taking place. The goal of our research was to use an innovative approach to identify nociceptor and immune cell-specific mechanisms in both the peripheral and central nervous systems that mediate sex differences during neuropathic pain development. Our findings suggest that the initial phase of neuropathic development is sexually dimorphic, characterized by nociceptor-specific signaling mechanisms in females and immune cell mediated sensitization in males which may be modulated by genetic and pharmacological manipulation of toll-like receptor 4 signaling.