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

项目主任/首席调查员(最后、第一、中间)：德特洛夫，梅根·瑞安 项目总结 脊髓损伤(SCI)损害感觉传递，导致慢性、衰弱的神经病理性疼痛。 慢性疼痛困扰着超过1亿美国人，给美国的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。而我们的 对慢性疼痛发生的分子基础的了解已经得到了改善，可用的 治疗提供的缓解是有限的。脊髓损伤后，康复运动训练在临床上得到广泛应用。 其主要目标是促进脊髓损伤后的运动恢复。在实验室中，我们已经展示了 锻炼对有意义的感觉恢复至关重要。早期进行持续的运动训练 脊髓损伤大鼠的程序防止神经病理性疼痛的发展，同时延迟类似的 运动训练直到确定疼痛时才能有效缓解疼痛。这段时间是从 损伤的发生也表明了背角的炎症程度。我们之前已经表明， 慢性脊髓损伤和神经病理性疼痛的发展与小胶质细胞激活的强劲增加相对应 以及促炎细胞因子的水平。这项提议寻求延长治疗窗口，在以下情况下 康复运动通过药理消炎成功抑制神经病理性疼痛 在背根神经节。我们将使用一种药物来抑制损伤引起的炎症。 急性脊髓损伤后，在脊髓损伤前和/或在脊髓损伤后同时开始运动。这将是 确定是否必须在开始运动之前减少炎症以抑制疼痛 在运动开始时，如果它的发展或足以调节炎症。我们将衡量 与外源性炎症环境相关的伤害性感受器电生理特性的变化 在背根节损伤后，在有无运动的情况下进行治疗。从这些信息中获得的信息 实验将指导未来优化运动治疗慢性脊髓损伤引起的疼痛的努力。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

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