Targeting neuropathic pain prevention: Modulating the neuroimmunology of peripheral nerve injury

项目总结 神经性疼痛在世界范围内以流行的比例发生，目前还没有可用的治疗方法 提供足够的疼痛缓解，而且都有显著的副作用。和所有人一样，没有一个人是“疾病修饰者” 只是针对症状的缓解，而不是原因。一定有更好的方法来控制疼痛。 我们的发现可能会给创伤和外科手术的临床治疗带来革命性的变化。 所有这些人都有发生神经性疼痛的明显风险(约50%-70%)。我们的发现是6周的 在神经损伤时停止的适度自愿运动似乎永久性地抑制了后来的- 急诊室神经病理性疼痛的发展。这种影响以前从未报道过。 这项建议的核心论点是，新的、优越的药理和/或草药治疗策略-- GES将产生于理解非药理学的自愿锻炼如何产生戏剧性的预防 慢性疼痛的症状。关键的第一步是了解VWR如何预防慢性疼痛。这启发了目标- ED，循证步骤，通过药物和/或实现同样戏剧性的疼痛预防 草药就要来了。本提案中探讨的机制不同于任何 目前可用的止痛药。如果我们能够理解和利用神经病理性疼痛的预防，这 应导致具有广泛实际重要性的早期药物干预。 6wk自愿车轮跑(VWR)如何深刻影响神经免疫学的级联 而由后来的神经损伤引发的神经病理事件从未被探索过。这对以下各项至关重要 在机械论层面上理解，因为先前的VWR似乎是控制疾病的第一个“疾病修正”方法。 是否会发展成慢性疼痛。了解这种情况是如何发生的将使新药的开发成为可能 这些疗法在药理学上复制了这些效果，而不需要很少有人参加的运动疗法. PLE将紧随其后。 我们预测，了解事先的自愿锻炼(VWR)如何发挥如此强大的、表面上看起来 永久抑制神经性疼痛是一个容易实现的研究目标，可以通过多学科来解决 提出了一种方法。这将首先寻求了解行为，免疫学，神经免疫学， 和功能效应：(A)VWR，(B)神经损伤(经典的坐骨神经慢性压迫损伤[CCI]模型 (C)它们在神经损伤后的相互作用。基于这些发现， 提出了机械论研究，以便开始探索先前的VWR如何施加如此积极的、痛苦的- 对晚期神经损伤的预防作用。为了实现这一目标，试图抑制和概括 提出了VWR效应的概念。长期目标是利用对先前VWR如何 创造了这种对神经病理性疼痛的长期抑制，从而确定了临床上相关的治疗神经性疼痛的方法 迷走式疼痛预防，从而提供了一种比目前可用的更好的疼痛控制方法。

PROJECT SUMMARY Neuropathic pain occurs in epidemic proportions worldwide and none of the currently available therapeutics provides adequate pain relief and all have significant side effects. None are “disease modifying” as all are simply palliative in targeting symptoms, not cause. There must be a better approach to pain control. What we have discovered could potentially revolutionize the clinical treatment of trauma and surgical pa- tients, all of whom are at marked risk (~50-70%) for developing neuropathic pain. Our discovery is that 6 wk of moderate voluntary exercise that ceases at the time of nerve trauma appears to permanently suppress the lat- er development of neuropathic pain. Such an effect has never been previously reported. The core thesis of this proposal is that novel, superior pharmacological and/or herbalism treatment strate- gies will arise from understanding how non-pharmacological voluntary exercise produces dramatic prevention of chronic pain. The critical first step is to understand how VWR prevents chronic pain. This enlightens target- ed, evidence-based steps toward achieving the same dramatic prevention of pain via pharmacological and/or herbal medicine approaches. The mechanisms explored in the present proposal are unique from those of any currently available pain therapeutic. If we can understand and harness prevention of neuropathic pain, this should lead to early drug interventions of broad practical importance. How 6 wk voluntary wheel running (VWR) could profoundly influence the cascade of neuroimmunological and neuropathological events set into motion by later nerve injury has never been explored. This is critical to understand at a mechanistic level, as prior VWR appears to be the first “disease modifying” approach to con- trolling whether chronic pain develops. Understanding how this occurs will enable development of novel drug regimens to pharmacologically duplicate these effects without the necessity of exercise regimens that few peo- ple will follow. We predict that understanding how prior voluntary exercise (VWR) exerts such powerful, and seemingly permanent suppression of neuropathic pain is a tractable research goal, addressable by the multi-disciplinary approach proposed. This would first seek to understand the behavioral, immunological, neuroimmunological, and functional effects of: (a) VWR, (b) nerve injury (classic sciatic chronic constriction injury [CCI] model in male and female rats), and (c) their interaction on the aftermath of nerve injury. Based on these findings, mechanistic studies are proposed so to begin to explore how prior VWR could exert such a positive, pain- preventative effect on later nerve injury. Toward this goal, studies that seek to inhibit and to recapitulate the effects of VWR are both proposed. The long term aim is to capitalize on the understanding of how prior VWR creates such long-lasting suppression of neuropathic pain so to identify clinically relevant approaches to neu- ropathic pain prevention, thereby providing a far superior approach to pain control than currently available.