Central Mechanisms involved in the interactions between muscle pain and exercise

描述(申请人提供)：有规律的体力活动(锻炼)可以减轻慢性肌肉骨骼疼痛的患者的疼痛；而不习惯的锻炼会加剧疼痛。人们对体力活动引起的疼痛反应的这种明显的二分法知之甚少，这使得疼痛患者的运动处方具有挑战性。在久坐不动的小鼠中，一次运动可以增强对阈值下肌肉刺激(pH 5.0生理盐水)的伤害性反应；这种增强可以通过5天的自愿转轮活动来阻止。此外，在小鼠中，通过8周的自愿转轮活动，可以防止由反复肌肉注射酸(pH 4.0)引起的慢性肌肉疼痛的发展。有规律的运动被认为激活中枢抑制通路，产生阿片介导的镇痛；延髓头端腹内侧核(RVM)是阿片诱导镇痛的关键中央核。然而，几乎没有数据支持中枢阿片类药物机制在运动诱导的镇痛中的作用，特别是在慢性疼痛的情况下。我们的初步数据显示，8周的跑轮活动(即定期运动)的镇痛效果被阿片受体的全身阻断所逆转，证实阿片类药物在常规运动诱导的镇痛中是重要的。我们的初步数据显示，在单次运动或诱导慢性肌肉疼痛后，久坐动物的RVM中有p-NR1(NMDA受体)增加。然而，rvm中p-NR1的这些增加可以通过定期运动来防止，这表明p-NR1受到运动激活机制的调节。这些数据导致了我们的中心假设，即定期运动增强了中枢抑制通路的激活，该通路利用内源性阿片类药物来调节RVM中的p-NR1。我们将通过以下具体目标来实现我们的核心目标。目标1将确定有规律的体力活动(跑轮运动)是否防止慢性肌肉疼痛的发展，以及这种影响是否与运动训练和激活RVM时可能发生的运动和自主神经反应有关。目标2将确定有规律的体育活动是否通过激活阿片受体来防止痛觉过敏的发展。我们将通过阿片受体的药理和遗传操作来测试这一点。目的3探讨非习惯性体力活动增强痛觉的神经回路和规律体力活动产生的镇痛作用。我们将确定NMDA受体是否位于并通过m-阿片受体(MOR)调节促进疼痛的“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调节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，以改善对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：有规律的体育活动(运动)可以减轻慢性肌肉骨骼疼痛患者的疼痛；而不习惯的运动会加剧疼痛。这项建议旨在利用最近开发的运动性疼痛和运动诱导止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，以改善对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。

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.