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

• 批准号: 10402776
• 负责人: KATHLEEN A SLUKA
• 金额: $ 50.67万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402776
• 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-1; Interleukin-1 Receptors; Interleukin-10; Lead; MicroRNAs; Mus; Muscle; Myalgia; Nociceptors; Pain; Pain management; Persons; Pharmacologic Substance; Pharmacology; 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; macrophage; nociceptive response; pain chronification; pain model; pain reduction; physical inactivity; prevent; receptor; response

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.

项目总结/摘要 在流行病学研究中，规律的体力活动与慢性疼痛的发生率降低有关;然而， 剧烈运动会加剧慢性疼痛患者的疼痛。在动物模型中，我们 显示单次运动增强了身体不活动小鼠对肌肉损伤的伤害性反应， 并且规律的身体活动防止慢性肌肉痛觉过敏的发展。的机制 在对身体活动的疼痛反应中驱动这种明显的二分法的机制知之甚少。我们建议 局部肌肉巨噬细胞的可塑性可以在很大程度上解释这种二分法。巨噬细胞释放 炎症或抗炎细胞因子，取决于两种相关表型：经典活化（M1） 巨噬细胞释放炎性细胞因子，调节性（M2）巨噬细胞释放抗炎性细胞因子， 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 有规律的体力活动改变了M1和M2巨噬细胞之间的平衡，导致更多的 抗炎细胞因子。疲劳的代谢产物，三磷酸腺苷（ATP）和质子，产生疼痛， 人和非活动动物的痛觉过敏，并激活表面受体，P2 X7和ASIC 3， 巨噬细胞我们的初步数据支持巨噬细胞在活动诱导的疼痛和活动中的作用， 诱导镇痛，并在定期运动后显示更大比例的M2。具体目标1将调查 巨噬细胞在不活动小鼠活动诱发的痛觉过敏中的作用。我们假设 肌肉巨噬细胞上的P2 X7或ASIC 3的激活在身体不活动的动物中释放IL-1 β， 痛觉过敏具体目标2将描述巨噬细胞在预防慢性肌肉疼痛中的作用， 有规律的身体活动。我们假设肌肉巨噬细胞上P2 X7或ASCI 3的激活释放了 IL-10在体力活动动物中产生镇痛作用。具体目标3将研究ATP、质子或其 组合产生培养的巨噬细胞从M1到M2的表型转换。我们假设 ATP和质子的组合是诱导从M1到M2巨噬细胞的表型转换所必需的。 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， 第一个确定先天免疫系统在活动诱导的痛觉过敏和镇痛中的作用。 了解这些机制对于了解疾病的发展和预防至关重要。 慢性疼痛，以及疼痛患者体力活动的后果。旨在减少 在最初的锻炼计划中，疼痛可能会导致更好地坚持保持有规律的身体活动 对于慢性疼痛的人。进一步的决定因素激活定期的身体活动， 内源性解决机制，是防止急性向慢性转变的关键组成部分 痛苦