Regulation of neuropathic pain by exercise: effects on nociceptor plasticity and inflammation

项目主任/主要研究者（最后，第一，中间）：Detloff，Megan Ryan 项目摘要 脊髓损伤（SCI）损害感觉传递，导致慢性神经性疼痛。 慢性疼痛困扰着超过1亿美国人，并给美国医疗保健系统带来了巨大的负担， 根据医学研究所最近的一份报告，每年花费超过5000亿美元。虽然我们的 对慢性疼痛发展的分子基础的理解已经提高， 治疗提供有限的缓解。脊髓损伤后，康复运动训练在临床上被广泛应用 其主要目标是促进SCI后的运动恢复。在实验室中，我们已经证明了 运动对有意义的感觉恢复至关重要。早期进行持续运动锻炼 在脊髓损伤大鼠中的一个程序可以防止神经性疼痛的发展，同时延缓类似的疼痛。 运动训练，直到疼痛建立是无效的改善它。时间流逝，因为 损伤的发生也表明背角的炎症程度。我们之前已经证明， 慢性SCI和神经性疼痛的发展与小胶质细胞活化的强烈增加相对应 以及促炎细胞因子的水平。该提案寻求延长治疗窗口， 康复运动可以通过减少炎症反应成功地抑制神经病理性疼痛 在背根神经节。我们会使用药物抑制损伤引起的炎症 在脊髓损伤后运动开始之前和/或同时，这将 确定在开始运动以抑制疼痛之前是否必须减少炎症 发展或是否足以在运动开始时调节炎症。我们将测量 与外源性炎症环境相关的伤害感受器电生理特性的变化 在脊髓损伤后的背根神经节在有或无运动作为一种治疗。从这些收集到的信息 实验将指导未来的努力，以优化慢性SCI引起的疼痛的治疗运动。 OMB编号0925 - 0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Detloff, Megan Ryan PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission leads to chronic, debilitating neuropathic pain. Chronic pain afflicts over 100 million Americans and creates an enormous burden on US health care systems, costing over half a trillion dollars annually according to a recent report from the Institute of Medicine. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. After SCI, rehabilitative locomotor training is widely used in the clinical SCI population with its primary goal to promote motor recovery after SCI. In the lab, we have shown the timing of exercise is critical to meaningful sensory recovery. Early administration of a sustained locomotor exercise program in spinal cord injured rats prevents the development of neuropathic pain, while delaying similar locomotor training until pain was established was ineffective at ameliorating it. The time elapsed since the injury occurred also indicates the degree of inflammation in the dorsal horn. We have previously shown that chronic SCI and the development of neuropathic pain correspond with robust increases in microglial activation and the levels of pro-inflammatory cytokines. This proposal seeks to lengthen the therapeutic window where rehabilitative exercise can successfully suppress neuropathic pain by pharmacologically reducing inflammation in dorsal root ganglia. We will administer a pharmacologic agent to dampen injury-induced inflammation acutely after SCI prior to and/or at the same time as exercise initiation after spinal cord injury. This will determine whether inflammation must be reduced prior to the initiation of exercise to suppress pain development or if it is sufficient to modulate inflammation at the time exercise is initiated. We will measure changes in the electrophysiological properties of nociceptors related to the extrinsic inflammatory environment in the DRG after SCI in the presence or absence of exercise as a treatment. Information garnered from these experiments would guide future efforts to optimize the treatment of chronic SCI-induced pain by exercise. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page