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

项目摘要/摘要 创伤性烧伤会产生由组织和神经损伤引起的极度疼痛， 伴随着炎症的夸张。必要的伤口护理程序，如清创、烧伤 切除、移植和动员只会增加这种痛苦。出于这些原因，创伤性烧伤带来的疼痛 出了名的难以管理；因此，目前的报告表明，与烧伤相关的疼痛目前治疗不足。 创伤性损伤会显著增加疼痛敏感性(痛觉过敏)，并加速发展 对阿片类镇痛剂的耐受性与非创伤性损伤的比较。不幸的是，驱动 创伤后增加的敏感性和耐受性尚不清楚。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向慢性疼痛的过渡成为一个重大问题。 研究主要集中在对伤害的先天免疫反应上；然而， 最近纳入了女性受试者，发现了不同性别在免疫调节疼痛敏感性方面的差异。 这些发现促使人们重新考虑性别对疼痛处理的影响，以及 仅限男性参与的研究才是真正适用的。众所周知，女性更有可能报告更剧烈的疼痛 和经历这种伤害后的慢性疼痛；然而，这些特定性别背后的机制 不同之处目前尚不清楚。此外，应激诱导的神经内分泌系统的适应是 被认为在急性和慢性疼痛结果的发病机制中起着重要作用。失调症 创伤后的下丘脑-垂体-肾上腺轴和交感肾上腺轴已被证明减少 调节内源性疼痛抑制和阿片类镇痛的下行通路的活动。我们 假设创伤性烧伤后疼痛的发病机制与免疫反应有关 通过神经内分泌系统的参与，以性别特有的方式进行调节。利用这些性爱- 具体的差异可能是理解如何治疗创伤性烧伤产生的疼痛的关键。性爱- 特定的基因、荷尔蒙和信号机制可能会揭示以前发现的新靶点 被忽视，给未来的针对性别的干预带来了巨大的希望。因此，拟议的研究方案 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 全层烧伤动物模型的反应性和神经内分泌反应。本节目 研究将使我们更深入地了解创伤性烧伤引起疼痛的机制 在治疗和识别背后的性相关驱动因素方面具有挑战性。我们在这个奖项的期限内的目标是 确定导致耐受性和痛觉过敏加速发展的性别特异性机制，并 洞察针对性别的干预措施的潜在目标，以治疗急性疼痛并防止过渡到 慢性疼痛。进行这些研究将建立一个强大的研究计划，定位于调查任何 我们可能发现的有希望的目标。

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.