Preventing Transition of Acute-to-Chronic Neuropathic Pain: Models, Mechanisms &

描述（由申请人提供）：虽然人们越来越认识到小胶质细胞和星形胶质细胞激活在产生和维持多种增强疼痛状态中的重要性，但尚未在疼痛增强的背景下探索的胶质细胞功能的一个重要方面是致敏或“引发”小胶质细胞反应的影响。来自疼痛领域之外的证据表明，小胶质细胞激活的过去历史可以显着改变它们对新挑战的反应。小神经胶质细胞可以通过各种挑战达到致敏状态，包括外周或中枢创伤/炎症、应激、先前疼痛和暴露于阿片类药物，其引人注目地是已知的急性疼痛向慢性疼痛（包括神经性疼痛）转变的共病。在这样一种准备状态下，小胶质细胞现在对新的挑战做出了戏剧性的过度反应，比以前更强大，更长。我们相信，这种导致神经胶质启动的先前挑战可以为外周和中枢神经损伤后急性疼痛向慢性疼痛的转变奠定基础，从而导致慢性神经性疼痛。引发的小胶质细胞的再激活可能导致从急性疼痛到慢性疼痛的转变，这是神经炎症反应的结果，其在幅度和持续时间上都大大放大。 目标. (1)根据本RFA的指定目标，基于第一次激发（Hit 1：外周或中枢创伤/炎症、应激、既往疼痛、暴露于阿片类药物）将显著增强后续（第二次）激发（Hit 2：外周或中枢神经炎症/损伤）诱导的疼痛的前提，开发新的大鼠模型，以研究从急性神经性疼痛向慢性神经性疼痛的转变。(2)利用完善的稳健模型来测试非阿片类药物、非成瘾性血脑屏障渗透性神经胶质激活抑制剂和消退素预防急性疼痛向慢性疼痛转变的潜力。(3)鉴于慢性自愿运动在创造对多种负面结果（包括限制神经胶质/免疫反应）的弹性方面产生了非常强大的积极影响，慢性自愿运动也将被测试其防止从急性疼痛转变为慢性疼痛的能力，这是一种通过与疼痛领域以外的专家合作实现的方法。Fleshner）。(4)发现细胞内的变化，区分大鼠从急性神经性疼痛转变为慢性神经性疼痛，并确定这些潜在的慢性疼痛的细胞标志物如何受到成功干预（胶质抑制剂，自愿运动）的影响。这将为识别和靶向可靠预测急性向慢性神经性疼痛转变的变化奠定基础。 公共卫生相关性：神经性疼痛在世界范围内流行，很少了解如何以及为什么急性疼痛转变为慢性疼痛。这个项目探讨了神经胶质致敏（“启动”）的假设，即为什么急性疼痛在外周或中枢神经损伤后会变成慢性疼痛。此外，它还探索了两种策略-一种是药理学（抑制神经胶质激活的药物; resolvins），一种是非药理学（疼痛发作前的自愿运动）-用于预防慢性疼痛的演变。

DESCRIPTION (provided by applicant): While there has been increasing recognition of the importance of microglial and astrocyte activation in the creation & maintenance of diverse enhanced pain states, an important aspect of glial functioning that has not yet been explored in the context of pain enhancement is the effect of a sensitized, or "primed", microglial response. Evidence has accrued from outside of the pain field that the past history of microglial activation can dramatically alter their response to new challenges. Microglia can reach a primed state via a variety of challenges, including peripheral or central trauma/inflammation, stress, prior pain, and exposure to opioids, which strikingly are known co-morbidities for the transition of acute to chronic pain, including neuropathic pain. While in such a primed state, microglia now dramatically over-respond to new challenges, stronger and longer than before. We believe such prior challenges that result in glial priming can set the stage for the transition of acute to chronic pain following peripheral & central neural damage, resulting in chronic neuropathic pain. Re-activation of primed microglia may lead to a transition from acute pain to chronic pain as a result of a neuroinflammatory response that is greatly amplified in both magnitude and duration. Goals. (1) In accordance with the specified goals of this RFA, develop new rat models to study the transition from acute to chronic neuropathic pain, based on the premise that a first challenge (Hit 1: peripheral or central trauma/inflammation, stress, prior pain, exposure to opioids) will markedly enhance pain induced by a subsequent (second) challenge (Hit 2: peripheral or central neural inflammation/injury). (2) Utilize the refined robust models to test the potential of non-opioid, non-addictive blood-brain barrier permeable glial activation inhibitors & resolvins to prevent the transition of acute to chronic pain. (3) Given the remarkably powerful positive effects produced by chronic voluntary exercise in creating resiliency to a multitude of negative outcomes (including constraining glial/immune reactivity), chronic voluntary exercise will also be tested for its ability to prevent the transition from acute to chronic pain, an approach enabled by teaming with an expert from outside the pain field (M. Fleshner). (4) Discover intracellular changes that differentiate rats which do vs. do not transition from acute to chronic neuropathic pain, & define how these potential cellular markers of impending chronic pain are affected by successful interventions (glial inhibitors, voluntary exercise). This will lay the groundwork for identifying and targeting changes reliably predictive of the transition of acute to chronic neuropathic pain. PUBLIC HEALTH RELEVANCE: Neuropathic pain occurs in epidemic proportions worldwide, with little understanding of how and why the transition of acute-to-chronic pain occurs. This project explores the hypothesis that glial sensitization ("priming) lies at the heart of the why acute pain can become chronic after peripheral or central neural damage. In addition, it explores two strategies - one pharmacological (drugs that inhibit glial activation; resolvins), one non-pharmacological (voluntary exercise prior to pain onset) - for preventing the evolution of chronic pain.