Central Mechanisms involved in the interactions between muscle pain and exercise

参与肌肉疼痛和运动之间相互作用的中枢机制

• 批准号: 8292800
• 负责人: KATHLEEN A SLUKA
• 金额: $ 46.84万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-06 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292800
• 关键词: Absence of pain sensation; Acids; Acute; Acute Pain; Address; Affect; Analgesics; Animal Model; Animals; Brain Stem; Cell Nucleus; Cell membrane; Cells; Chronic; Complex; Data; Development; Exercise; Goals; Health Benefit; Hyperalgesia; Individual; Injection of therapeutic agent; Intramuscular; Laboratories; Link; Mediating; Modeling; Motor; Mus; Muscle; Musculoskeletal Pain; Myalgia; N-Methyl-D-Aspartate Receptors; NR1 NMDA receptor; NR1 gene; Neurobiology; Nociception; Opioid; Opioid Receptor; Pain; Pathway interactions; Peripheral; Phosphorylation; Physical activity; Prevention; Receptor Cell; Research; Role; Running; Saline; Spinal Cord; Stimulus; Sympathetic Nervous System; Testing; Training; Work; chronic pain; endogenous opioids; genetic manipulation; improved; mouse development; neural circuit; nociceptive response; pain behavior; prevent; programs; research study; response; sedentary; trafficking

DESCRIPTION (provided by applicant): Regular physical activity (exercise) can reduce pain in people with chronic musculoskeletal pain; whereas, unaccustomed exercise can exacerbate pain. This apparent dichotomy in pain response to physical activity is poorly understood, making exercise prescription for individuals with pain challenging. In sedentary mice, a single bout of exercise enhances the nociceptive response to subthreshold muscle stimuli (pH 5.0 saline); this enhancement is prevented by 5 days of voluntary running wheel activity. Further, in mice the development of chronic muscle pain, induced by repeated intramuscular acid (pH 4.0) injections, is prevented by 8 weeks of voluntary running wheel activity. Regular exercise is believed to activate central inhibitory pathways that produce an opioid-mediated analgesia; the rostral ventromedial medulla (RVM) is a key central nucleus in opioid-induced analgesia. However, little data is available to support a role for central opioid mechanisms in exercise-induced analgesia, particularly in conditions of chronic pain. Our preliminary data show that the analgesic effect of 8 weeks of running wheel activity (i.e. regular exercise) is reversed by systemic blockade of opioid receptors, establishing that opioids are important in regular exercise-induced analgesia. Our preliminary data show that there is increased p-NR1 (NMDA receptor) in the RVM in sedentary animals after a single-bout of exercise or induction chronic muscle pain. These increases in p-NR1 in the RVM, however, are prevented by regular exercise, suggesting that p-NR1 is modulated by mechanisms activated by exercise. These data led to our central hypothesis that regular exercise enhances activation of central inhibitory pathways that utilize endogenous opioids to modulate p-NR1 in the RVM. We will address our central aim through the following specific aims. Aim 1 will determine if regular physical activity (running wheel exercise) prevents the development of chronic muscle pain, and if such an effect is associated with motor and autonomic responses that might occur in response to exercise training and activation of the RVM. Aim 2 will determine if regular physical activity prevents the development of hyperalgesia by activation of opioid receptors. We will test this by pharmacological and genetic manipulation of opioid receptors. Aim 3 will explore the neural circuitry involved in the enhanced nociception to unaccustomed physical activity and the analgesia produced by regular physical activity. We will establish if NMDA receptors are located on and modulate pain facilitatory "ON cells" through m- opioid receptors (MOR), and if these cells project to the spinal cord. These studies will be the first to evaluate the effects of regula exercise on hyperalgesia and the underlying mechanisms that mediate these effects. Understanding these interactions will give us a better understanding of the underlying neurobiology to improve the overall management of people with chronic musculoskeletal pain, and prevention of development of chronic pain. PUBLIC HEALTH RELEVANCE: Regular physical activity (exercise) can reduce pain in people with chronic musculoskeletal pain; whereas, unaccustomed exercise can exacerbate pain. This proposal aims to examine the central mechanisms underlying the effects of exercise on pain using recently developed animal models of exercise-induced pain, and exercise-induced analgesia. Understanding these interactions will give us a better understanding of the underlying neurobiology to improve the overall management of people with chronic musculoskeletal pain, and prevention of development of chronic pain.

描述（由申请人提供）：定期进行体力活动（锻炼）可以减轻慢性肌肉骨骼疼痛患者的疼痛；然而，不习惯的运动会加剧疼痛。人们对身体活动对疼痛反应的这种明显的二分法知之甚少，这使得为疼痛患者制定运动处方具有挑战性。在久坐的小鼠中，单次运动可增强对阈下肌肉刺激（pH 5.0 盐水）的伤害性反应；这种增强是通过 5 天的自愿跑轮活动来阻止的。此外，在小鼠中，通过重复肌内注射酸（pH 4.0）引起的慢性肌肉疼痛的发展，可以通过 8 周的自愿跑轮活动来预防。定期运动被认为可以激活中枢抑制通路，从而产生阿片类药物介导的镇痛作用；延髓头端腹内侧（RVM）是阿片类药物诱导镇痛的关键中枢核。然而，很少有数据支持中枢阿片类药物机制在运动引起的镇痛中的作用，特别是在慢性疼痛的情况下。我们的初步数据表明，8周跑轮活动（即定期运动）的镇痛效果可通过阿片受体的全身阻断而逆转，这表明阿片类药物在定期运动引起的镇痛中很重要。我们的初步数据表明，在一次运动或诱发慢性肌肉疼痛后，久坐动物的 RVM 中 p-NR1（NMDA 受体）增加。然而，定期运动可以阻止 RVM 中 p-NR1 的增加，这表明 p-NR1 受到运动激活机制的调节。这些数据得出我们的中心假设，即定期运动可以增强中枢抑制途径的激活，利用内源性阿片类药物调节 RVM 中的 p-NR1。我们将通过以下具体目标来实现我们的中心目标。目标 1 将确定定期的体力活动（跑轮运动）是否可以预防慢性肌肉疼痛的发生，以及这种效应是否与运动训练和 RVM 激活时可能发生的运动和自主反应相关。目标 2 将确定定期体力活动是否可以通过激活阿片受体来防止痛觉过敏的发生。我们将通过阿片受体的药理学和基因操作来测试这一点。目标 3 将探索与不习惯的体力活动增强的伤害感受和常规体力活动产生的镇痛有关的神经回路。我们将确定 NMDA 受体是否位于并通过 m-阿片受体 (MOR) 调节疼痛促进“ON 细胞”，以及这些细胞是否投射到脊髓。这些研究将首次评估调节运动对痛觉过敏的影响以及介导这些影响的潜在机制。了解这些相互作用将使我们更好地了解潜在的神经生物学，从而改善慢性肌肉骨骼疼痛患者的整体管理，并预防慢性疼痛的发展。 公共卫生相关性：定期进行体力活动（锻炼）可以减轻慢性肌肉骨骼疼痛患者的疼痛；然而，不习惯的运动会加剧疼痛。该提案旨在利用最近开发的运动引起的疼痛和运动引起的镇痛的动物模型来研究运动对疼痛影响的核心机制。了解这些相互作用将使我们更好地了解潜在的神经生物学，从而改善慢性肌肉骨骼疼痛患者的整体管理，并预防慢性疼痛的发展。