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

以预防神经病理性疼痛为目标：调节周围神经损伤的神经免疫学

基本信息

批准号：
10062833
负责人：
LINDA WATKINS
金额：
$ 34.65万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062833
关键词：
Acute Adoptive Transfer Adult American Anti-Inflammatory Agents Antioxidants Behavioral Blood Blood-Nerve Barrier Calpain Cells Centers for Disease Control and Prevention (U.S.)Clinical Treatment Development Disease Dose Epidemic Event Exercise Female Goals Herbal Medicine Herbalism Human Immune Immune response Immunologics Injury Interleukin-10 Intervention Lead Leisures MMP9 gene Mediator of activation protein Modeling Moderate Exercise Motion Nerve Nitric Oxide Operative Surgical Procedures Oxidative Stress Pain Pain management Patients Peripheral nerve injury Pharmaceutical Preparations Pharmacology Prevention Rattus Recommendation Regimen Reporting Research Resolution Risk Running Side Site Symptoms Therapeutic Time Trauma base cell type chronic constriction injury chronic pain clinically relevant cost cytokine endogenous opioids evidence base exercise regimen inhibitor/antagonist interdisciplinary approach male monocyte nerve injury neuroimmunology neutrophil novel novel therapeutics pain relief painful neuropathy palliative pill prevent sciatic nerve sedentary side effect statistics treatment strategy

项目摘要

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.

项目概要神经性疼痛在世界范围内流行，目前尚无可用的治疗方法可以提供足够的疼痛缓解，并且所有药物都具有显着的副作用，但它们都不是“疾病缓解”。只是缓解症状，而不是病因。必须有更好的方法来控制疼痛。我们的发现可能会彻底改变创伤和外科手术的临床治疗。我们的发现是，所有患者都有发生神经性疼痛的显着风险（约 50-70%）。在神经损伤时停止的适度自愿运动似乎会永久抑制背部以前从未报道过这种效应。该提案的核心论点是新颖的、优越的药理学和/或草药治疗策略了解非药物自愿锻炼如何产生显着的预防作用将会产生效果关键的第一步是了解 VWR 如何预防慢性疼痛。 ed、基于证据的步骤，通过药物和/或方法实现同样显着的疼痛预防本提案探讨的机制与任何其他方法都是独一无二的。如果我们能够了解并利用目前可用的疼痛治疗方法来预防神经性疼痛，应导致具有广泛实际意义的早期药物干预。 6 周自愿轮跑 (VWR) 如何深刻影响神经免疫级联反应神经病理学事件由后来的神经损伤引发，这一点至关重要。在机械层面上理解，因为之前的 VWR 似乎是第一个“疾病修饰”方法了解慢性疼痛是否会发生将有助于开发新药物。药物疗法可以在药理上复制这些效果，而无需进行很少有人需要的锻炼疗法 ple将跟随。我们预测，了解先前的自愿锻炼（VWR）如何发挥如此强大的作用，并且看似永久抑制神经性疼痛是一个易于处理的研究目标，可以通过多学科的研究来解决提出的方法首先寻求了解行为、免疫学、神经免疫学、和功能影响：(a) VWR，(b) 神经损伤（经典坐骨神经慢性压迫性损伤 [CCI] 模型）雄性和雌性大鼠），以及（c）它们在神经损伤后的相互作用。提出了机制研究，以便开始探索先前的 VWR 如何发挥如此积极的、痛苦的作用。为了实现这一目标，研究试图抑制和重现神经损伤。长期目标是利用对先前 VWR 的理解。对神经性疼痛产生如此持久的抑制，从而确定神经性疼痛的临床相关方法预防病理性疼痛，提供了比目前可用的更好的疼痛控制方法。