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

创伤性烧伤后疼痛性别差异的免疫和神经内分泌介质

• 批准号: 10789498
• 负责人: Jennifer E. Nyland
• 金额: $ 14.82万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10789498
• 关键词: Acceleration; Acute Pain; Adrenal Glands; Anhedonia; Animal Model; Anxiety; Automobile Driving; Award; Behavior; Behavioral Assay; Behavioral Model; Burn injury; Burning Pain; Cerebral cortex; Communities; Darkness; Data Analyses; Data Collection; Debridement; Development; Equipment; Excision; Female; Food; Future; Generations; Genes; Goals; Grant; Hormones; Human; Hyperalgesia; Hypothalamic structure; Immune; Immune response; Inflammation; Injury; Innate Immune Response; Intervention; Investigation; Knowledge; Lead; Light; Measurement; Measures; Mediator; Mental Depression; Modeling; Motivation; Neurosecretory Systems; Operant Conditioning; Opioid Analgesics; Outcome Study; Pain; Pain Measurement; Parents; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase I Clinical Trials; Pituitary Gland; Play; Positioning Attribute; Pre-Clinical Model; Procedures; Protocols documentation; Rattus; Reflex action; Reporting; Reproducibility; Research; Rewards; Rodent; Role; Running; Self Administration; Sensory; Sex Differences; Signal Transduction; Sleep disturbances; Stress; Survivors; Technology; Therapeutic; Thermal Hyperalgesias; Thick; Tissues; Trauma; Traumatic injury; Withdrawal; Woman; Work; chronic pain; conditioned place preference; experience; gait examination; immunoregulation; improved; insight; interest; male; mechanical allodynia; men; nerve damage; novel; pain behavior; pain chronification; pain inhibition; pain model; pain outcome; pain processing; pain sensitivity; pre-clinical; preference; prevent; programs; response; response to injury; sex; success; wound care

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.

项目概要/摘要 外伤性烧伤会因组织和神经损伤而产生难以忍受的疼痛， 伴随着炎症的加剧。必要的伤口护理程序，如清创、烧伤 切除、移植和活动只会增加这种痛苦。由于这些原因，外伤性烧伤引起的疼痛是 众所周知，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。 创伤性损伤会显着增加疼痛敏感性（痛觉过敏）并加速发展 与非创伤性损伤相比，对阿片类镇痛药的耐受性。不幸的是，驱动机制 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，使得从急性疼痛到慢性疼痛的转变成为烧伤后的一个重要问题。 研究主要集中在对损伤的先天免疫反应作为主要候选者；然而， 最近纳入女性受试者发现了免疫调节疼痛敏感性的性别特异性差异。 这些发现导致人们重新考虑性对疼痛处理的影响以及身体是否 仅限男性的研究确实适用。众所周知，女性更有可能报告更严重的疼痛 并在此类伤害后经历慢性疼痛；然而，这些性别特异性背后的机制 差异目前未知。此外，压力引起的神经内分泌系统的适应是 据信在急性和慢性疼痛的发病机制中发挥着重要作用。失调的 外伤后下丘脑-垂体-肾上腺和交感肾上腺轴已被证明会减少 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 假设涉及创伤性烧伤后疼痛发病机制的免疫反应是 通过神经内分泌系统的参与以性别特异性方式进行调节。利用这些性- 具体差异可能是了解如何治疗创伤性烧伤引起的疼痛的关键。性别- 特定的基因、激素和信号机制可能有助于揭示以前发现的新靶点 被忽视，这给未来针对性别的干预措施带来了很大希望。因此，拟议的研究计划 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 全层热烧伤动物模型的反应性和神经内分泌反应。这个节目 的研究将使我们更深入地了解外伤性烧伤造成疼痛的机制，从而 治疗和识别其背后与性相关的驱动因素具有挑战性。我们在该奖项期间的目标是 确定加速发展耐受性和痛觉过敏的性别特异性机制，并 深入了解针对特定性别的干预措施的潜在目标，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有力的研究计划，旨在调查任何 我们可能会发现有希望的目标。