Immune and neuroendocrine mediators of sex-differences in pain following traumatic burn injury

PROJECT SUMMARY/ABSTRACT Traumatic burn injuries generate excruciating pain resulting from tissue and nerve damage and the accompanying exaggeration of inflammation. Necessary wound care procedures such as debridement, burn excision, grafting, and mobilization only add to this pain. For these reasons, pain from traumatic burn injury is notoriously difficult to manage; hence current reports suggest that burn-related pain is currently undertreated. Traumatic injuries have a dramatic increase in pain sensitivity (hyperalgesia) and accelerated development of tolerance to opioid analgesics compared with non-traumatic injuries. Unfortunately, the mechanisms driving increased sensitivity and tolerance following trauma are unclear. Furthermore, over half of all burn survivors develop chronic pain, making the transition from acute to chronic pain a significant concern following burn injury. Research has primarily focused on the innate immune response to injury as a leading candidate; however, the recent inclusion of female subjects has uncovered sex-specific differences in immune-modulated pain sensitivity. These findings have led to reconsideration of the influence of sex on pain processing and whether the body of male-only research is truly applicable. It is well known that females are more likely to report more severe pain and to experience chronic pain following such injuries; however, the mechanisms behind these sex-specific differences are currently unknown. Additionally, stress-induced adaptations in the neuroendocrine system are believed to play an essential role in the pathogenesis of acute and chronic pain outcomes. Dysregulation of the hypothalamic-pituitary-adrenal and sympathoadrenal axes following traumatic injury has been shown to reduce the activity of descending pathways that modulate endogenous pain inhibition and opioid analgesia. We hypothesize that the immune response involved in the pathogenesis of pain following traumatic burn injury is regulated in a sex-specific manner through involvement of the neuroendocrine system. Exploiting these sex- specific differences may be key to understanding how to treat pain generated from traumatic burn injuries. Sex- specific genes, hormones, and signaling mechanisms may shed light on novel targets that have been previously overlooked, giving great hope for future sex-specific interventions. Accordingly, the proposed research program will address this critical gap in our understanding by systematically investigating the role of sex-specific immune reactivity and neuroendocrine responses in an animal model of full-thickness thermal burn injury. This program of research will lead us closer to understanding mechanisms that make pain from traumatic burn injuries so challenging to treat and identify sex-related drivers behind them. Our goal over the duration of this award is to identify sex-specific mechanisms underlying the accelerated development of tolerance and hyperalgesia and to provide insight to potential targets for sex-specific interventions to treat acute pain and prevent the transition to chronic pain. Conduct of these studies will build a robust program of research positioned to investigate any promising targets we may uncover.