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

描述(由申请人提供)：虽然越来越多的人认识到小胶质细胞和星形胶质细胞的激活在创造和维持各种增强的疼痛状态中的重要性，但在疼痛增强的背景下，神经胶质功能的一个重要方面尚未被探索，那就是敏化的或“启动的”小胶质细胞反应的影响。来自疼痛领域以外的证据表明，过去的小胶质细胞激活历史可以极大地改变他们对新挑战的反应。小胶质细胞可以通过各种挑战达到启动状态，包括外周或中枢创伤/炎症、应激、既往疼痛和阿片类药物的暴露，这些都是已知的急性疼痛向慢性疼痛(包括神经病理性疼痛)过渡的共病。在这种准备状态下，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、更持久。我们相信，这些导致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过渡奠定基础，从而导致慢性神经病理性疼痛。启动的小胶质细胞的重新激活可能导致从急性疼痛到慢性疼痛的转变，这是神经炎性反应的结果，这种反应在幅度和持续时间上都被大大放大。目标。(1)根据本RFA的具体目标，建立新的大鼠模型以研究从急性神经病理性疼痛到慢性神经性疼痛的转变，前提是第一次挑战(HIT 1：周围或中枢创伤/炎症、应激、先前的疼痛、接触阿片类药物)将显著增强随后(第二次)挑战(HIT 2：周围或中枢神经炎症/损伤)引起的疼痛。(2)利用改进的Robust模型测试非阿片类、非成瘾性血脑屏障通透性神经胶质激活抑制剂&解决素预防急性疼痛向慢性疼痛转变的可能性。(3)鉴于长期自愿锻炼在创造对多种负面结果(包括抑制神经胶质/免疫反应)的弹性方面产生的非常强大的积极影响，慢性自愿锻炼还将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(M.Fleshner)。(4)发现细胞内的变化，区分哪些大鼠有或没有从急性神经病理性疼痛过渡到慢性神经病理性疼痛，并确定这些即将到来的慢性疼痛的潜在细胞标记物如何受到成功的干预措施(神经胶质抑制药、自愿运动)的影响。这将为识别和定位变化奠定基础，可靠地预测急性神经病理性疼痛向慢性神经性疼痛的转变。

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.