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; 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.

项目摘要/摘要 常规的体育活动与流行病学研究中慢性疼痛的发生率降低有关。然而， 急性运动会加剧慢性疼痛患者的疼痛。在动物模型中类似，我们 显示一次锻炼可以增强对身体不活跃小鼠肌肉侮辱的伤害性反应， 这种规律的身体活动阻止了慢性肌肉痛觉过敏的发展。机制 在对体育锻炼的疼痛反应中推动这种明显的二分法知之甚少。我们提出了这个 二分法可能在很大程度上可以用局部肌肉巨噬细胞的可塑性来解释。巨噬细胞释放 炎症或抗炎细胞因子取决于两种相关表型：经典激活（M1） 巨噬细胞释放炎症细胞因子和调节（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 常规的体育锻炼会改变M1和M2巨噬细胞之间的平衡，从而更大的释放 抗炎细胞因子。疲劳代谢产物，三磷酸腺苷（ATP）和质子，会导致疼痛 人类和无活性动物中的痛觉过敏，并激活表面受体P2X7和ASIC3，ON 巨噬细胞。我们的初步数据支持巨噬细胞在活性引起的疼痛和活性中的作用 - 定期运动后诱导镇痛并显示出更大比例的M2。具体目标1将调查 巨噬细胞在活性小鼠中活性诱导的痛觉过敏中的作用。我们假设这一点 在肌肉巨噬细胞上激活P2X7或ASIC3在物理动物中释放IL-1以产生 痛苦。特定的目标2将表征巨噬细胞在预防慢性肌肉疼痛中的作用 定期体育锻炼。我们假设在肌肉巨噬细胞上激活P2X7或ASCI3 在身体活跃的动物中IL-10产生镇痛。特定目标3将调查ATP，质子或其 组合在培养的巨噬细胞中从M1到M2产生表型转换。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的必要条件。 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，因此将是 第一个确定先天免疫系统在活性引起的痛觉过敏和镇痛中的作用。 了解这些机制对于理解和预防的发展和预防至关重要 慢性疼痛以及疼痛个体体育锻炼的后果。旨在减少的治疗 初始锻炼计划中的疼痛可能会导致更好地依从性地保持常规体育锻炼 对于慢性疼痛的人。进一步的确定因素通过常规体育锻炼激活的因素，该因素激活 内源分辨率机制，是防止从急性到慢性过渡的关键组成部分 疼痛。