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: 8827245
• 负责人: KATHLEEN A SLUKA
• 金额: $ 43.25万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827245
• 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.

描述（由申请人提供）：定期体育锻炼（锻炼）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。对体育锻炼的疼痛反应中这种明显的二分法知之甚少，这使得疼痛挑战的人的运动处方。在久坐的小鼠中，一次运动可以增强对亚阈值肌肉刺激的伤害性反应（pH 5.0盐水）；这种增强是由5天的自愿跑轮活动阻止的。此外，在小鼠中，由重复的肌肉内酸（pH 4.0）注射引起的慢性肌肉疼痛的发育是由8周的自愿跑步车轮活性阻止的。据信定期运动会激活产生阿片类药物介导的镇痛的中心抑制途径。鼻腹髓质（RVM）是阿片类药物诱导的镇痛的关键中心核。但是，很少有数据可以支持运动引起的镇痛中中央阿片类药物机制的作用，尤其是在慢性疼痛的情况下。我们的初步数据表明，8周跑步车轮活动的镇痛作用（即定期运动）被全身阻断阿片受体逆转，确定阿片类药物在常规运动诱导的镇痛中很重要。我们的初步数据表明，在一次性运动或诱导慢性肌肉疼痛之后，RVM中RVM中的P-NR1（NMDA受体）增加。然而，RVM中P-NR1的这些增加是通过定期运动来阻止的，这表明P-NR1是通过锻炼激活的机制调节的。这些数据导致了我们的中心假设，即定期运动增强了使用内源性阿片类药物调节RVM中P-NR1的中心抑制途径的激活。我们将通过以下特定目标来解决我们的中心目标。 AIM 1将确定定期的体育锻炼（跑步运动）是否可以防止慢性肌肉疼痛的发展，以及是否与运动训练和RVM激活可能发生的运动和自主反应有关。 AIM 2将确定常规体育锻炼是否通过激活阿片受体的激活来阻止痛觉过敏的发展。我们将通过对阿片受体的药理和遗传操纵进行测试。 AIM 3将探索与未习惯的体育活动增强的伤害感受和常规身体活动产生的镇痛的神经回路。我们将确定NMDA受体是否位于并通过M-阿片类受体（MOR）调节疼痛的“细胞上”，以及这些细胞是否投射到脊髓上。这些研究将是第一个评估调节锻炼对痛觉过敏的影响以及介导这些作用的潜在机制的研究。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。