Role of macrophages in activity-induced pain and analgesia

巨噬细胞在活动引起的疼痛和镇痛中的作用

基本信息

批准号：
10615884
负责人：
KATHLEEN A SLUKA
金额：
$ 49.96万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615884
关键词：
ASIC channel Absence of pain sensation Acute Address Adenosine Triphosphate Adherence Analgesics Animal Model Animals Anti-Inflammatory Agents Automobile Driving Biology Cells Chronic Clinical Data Development Down-Regulation Equilibrium Exercise Fatigue Human Hyperalgesia Immune Immune response Immune system Incidence Individual Inflammatory Innate Immune System Interleukin-10 Interleukins Macrophage Mus Muscle Myalgia Nociceptors Pain Pain management Persons Pharmacologic Substance Phenotype Physical activity Prevention Protons Publishing Purinoceptor Receptor Activation Resolution Role Surface Testing Viral chronic musculoskeletal pain chronic pain cytokine epidemiology study exercise program improved microRNA delivery nociceptive response pain chronification pain model pain reduction pharmacologic physical inactivity prevent receptor response

项目摘要

Project Summary/ Abstract Regular physical activity is associated with reduced incidence of chronic pain in epidemiological studies; yet, an acute bout of exercise can exacerbate pain in those with chronic pain. Analogously in animal models, we show a single bout of exercise enhances the nociceptive response to muscle insult in physically inactive mice, and that regular physical activity prevents the development of chronic muscle hyperalgesia. The mechanisms driving this apparent dichotomy in pain response to physical activity are poorly understood. We propose this dichotomy may in large part be explained by the plasticity of local muscle macrophages. Macrophages release inflammatory or anti-inflammatory cytokines depending on two relevant phenotypes: classically-activated (M1) macrophages release inflammatory cytokines and regulatory (M2) macrophages release anti-inflammatory cytokines. The relative proportion of macrophage phenotype dictates the immune response, and we propose that regular physical activity shifts the balance between M1 and M2 macrophages to result in greater release of anti-inflammatory cytokines. Fatigue metabolites, adenosine triphosphate (ATP) and protons, produce pain in humans and hyperalgesia in inactive animals, and activate surface receptors, P2X7 and ASIC3, on macrophages. Our preliminary data support a role for macrophages in both activity-induced pain and activity- induced analgesia and show a greater proportion of M2s after regular exercise. Specific Aim 1 will investigate the role of macrophages in activity-induced hyperalgesia in physically inactive mice. We hypothesize that activation of P2X7 or ASIC3 on muscle macrophages releases IL-1 in physically inactive animals to produce hyperalgesia. Specific Aim 2 will characterize the role of macrophages in prevention of chronic muscle pain by regular physical activity. We hypothesize that activation of P2X7 or ASCI3 on muscle macrophages releases IL-10 in physically active animals to produce analgesia. Specific Aim 3 will investigate if ATP, protons, or their combination produces a phenotypic switch in cultured macrophages from M1 to M2. We hypothesize that the combination of ATP and protons is necessary to induce the phenotypic switch from M1 to M2 macrophages. These studies will examine the interactions between muscle, macrophages, and nociceptors and thus will be the first to determine the role of the innate immune system in activity-induced hyperalgesia and analgesia. Understanding these mechanisms is critically important to understanding the development and prevention of chronic pain, and the consequences of physical activity in individuals with pain. Treatments aimed at reducing pain during an initial exercise program could lead to better adherence in maintaining regular physical activity for people with chronic pain. Further determining factors activated by regular physical activity, which activates endogenous resolution mechanisms, is a critical component to preventing the transition from acute to chronic pain.

项目概要/摘要流行病学研究表明，定期进行体育活动与慢性疼痛的发生率降低有关；剧烈的运动会加剧慢性疼痛患者的疼痛，与动物模型类似。显示单次运动可以增强不活动小鼠对肌肉损伤的伤害性反应，定期的体力活动可以预防慢性肌肉痛觉过敏的发生。我们对身体活动引起的疼痛反应这种明显的二分法知之甚少。这种二分法在很大程度上可以用局部肌肉巨噬细胞释放的可塑性来解释。炎症或抗炎细胞因子取决于两种相关表型：经典激活 (M1) 巨噬细胞释放炎症细胞因子，调节性（M2）巨噬细胞释放抗炎细胞因子巨噬细胞表型的相对比例决定了免疫反应，我们建议定期的体力活动会改变 M1 和 M2 巨噬细胞之间的平衡，从而导致更多的释放抗炎细胞因子、疲劳代谢物、三磷酸腺苷 (ATP) 和质子会产生疼痛。人类和不活动动物的痛觉过敏以及激活的表面受体 P2X7 和 ASIC3 我们的初步数据支持巨噬细胞在活动引起的疼痛和活动引起的疼痛中的作用。诱导镇痛并在定期运动后显示出更大比例的 M2。具体目标 1 将进行研究。巨噬细胞在不活动小鼠活动诱发的痛觉过敏中的作用。肌肉巨噬细胞上的 P2X7 或 ASIC3 激活会在身体不活动的动物中释放 IL-1，从而产生具体目标 2 将通过以下方式描述巨噬细胞在预防慢性肌肉疼痛中的作用。我们勇敢地面对肌肉巨噬细胞上 P2X7 或 ASCI3 的激活。 IL-10 在体力活跃的动物中产生镇痛作用具体目标 3 将研究 ATP、质子或其是否具有镇痛作用。组合在培养的巨噬细胞中产生从 M1 到 M2 的表型转换。 ATP 和质子的结合是诱导 M1 巨噬细胞表型转变为 M2 巨噬细胞所必需的。这些研究将检查肌肉、巨噬细胞和伤害感受器之间的相互作用，因此将第一个确定先天免疫系统在活动引起的痛觉过敏和镇痛中的作用。了解这些机制对于理解疾病的发生和预防至关重要慢性疼痛，以及旨在减轻疼痛的体力活动的后果。初始锻炼计划期间的疼痛可能会导致更好地坚持定期体育活动对于患有慢性疼痛的人来说，进一步确定由定期体力活动激活的因素，从而激活。内源性解决机制，是防止急性向慢性转变的关键组成部分疼痛。