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

项目总结/摘要 创伤性烧伤产生由组织和神经损伤引起的剧痛， 伴随着炎症的加剧。必要的伤口护理程序，如清创、烧伤 切除、移植和移动只会增加这种痛苦。由于这些原因，创伤性烧伤的疼痛是 众所周知难以控制;因此目前的报道表明烧伤相关疼痛目前治疗不足。 创伤性损伤具有疼痛敏感性（痛觉过敏）的急剧增加和疼痛的加速发展。 与非创伤性损伤相比，对阿片类镇痛药的耐受性。不幸的是， 创伤后敏感性和耐受性的增加尚不清楚。此外，超过一半的烧伤幸存者 发展为慢性疼痛，使烧伤后从急性疼痛转变为慢性疼痛成为一个重要问题。 研究主要集中在对损伤的先天免疫反应上，作为主要候选者;然而， 最近纳入的女性受试者揭示了免疫调节疼痛敏感性的性别特异性差异。 这些发现促使人们重新思考性对疼痛处理的影响，以及性行为是否会影响身体的疼痛处理。 只针对男性的研究确实适用。众所周知，女性更容易报告更严重的疼痛 并经历这种伤害后的慢性疼痛;然而，这些性别特异性背后的机制 差异目前尚不清楚。此外，神经内分泌系统中的应激诱导的适应性是 据信在急性和慢性疼痛结果的发病机制中起重要作用。失调 创伤性损伤后的下丘脑-垂体-肾上腺和交感肾上腺轴已经显示出降低， 调节内源性疼痛抑制和阿片类镇痛的下行通路的活性。我们 假设创伤性烧伤后疼痛发病机制中涉及的免疫反应是 通过神经内分泌系统的参与，以性别特异性的方式进行调节。利用这些性- 具体的差异可能是理解如何治疗创伤性烧伤引起的疼痛的关键。性- 特定的基因、激素和信号传导机制可能会揭示以前研究过的新靶点， 这给未来针对性别的干预措施带来了很大希望。因此，建议的研究计划 我将通过系统地研究性别特异性免疫的作用来解决我们理解中的这一关键差距。 反应性和神经内分泌反应在全层热烧伤的动物模型。这个程序 的研究将使我们更接近理解创伤性烧伤疼痛的机制， 治疗和识别其背后与性有关的驱动因素具有挑战性。我们的目标是在这个奖项的持续时间是 确定性别特异性机制的耐受性和痛觉过敏的加速发展， 提供对性别特异性干预的潜在靶点的见解，以治疗急性疼痛并防止向 慢性疼痛这些研究的进行将建立一个强大的研究计划，以调查任何 我们可能会发现的目标

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.