Spinal Microglial Mechanisms of Visceral Hypersensitivity

描述(申请人提供)：源于内脏器官如胃或肠道的疼痛是一种病理警报，例如，与炎症性肠道疾病相关的疼痛，包括克罗恩病和溃疡性结肠炎。尽管最近在使用全身或局部抗炎疗法治疗结肠炎方面取得了进展，但许多患者仍然抱怨顽固性内脏疼痛。在结肠炎大鼠模型中，我们建议通过阻断中枢神经系统中新的细胞和分子靶点，在行为和神经元水平上逆转伤害性信号。我们假设，在实验性结肠炎大鼠中，脊髓中免疫原性小胶质细胞被激活并释放促炎介质，从而增强内脏感觉神经元的兴奋性，导致伤害性行为。我们进一步假设，激活的小胶质细胞，而不是其他类型的脊髓细胞，选择性地表达应激激活蛋白p38和三磷酸腺苷受体P2X4，而阻断这些信号通路会减弱神经元的过度兴奋性和内脏伤害性的行为迹象。这些研究将帮助我们开始确定远离(脊髓内)和与初始病理器官(结肠)截然不同的药物干预部位，以提高生物疗法的止痛效力，同时将不良副作用降至最低。 与公共卫生相关：内脏器官(如胃或肠道等“内部”器官)的炎症或损伤通常与令人不快的内脏痛感有关。某些形式的内脏疼痛，如结肠炎引起的疼痛，无法有效治疗。为了改善顽固性内脏疼痛的治疗选择，我们在这项应用中展示了通过阻断脊髓中新的细胞和分子靶点成功逆转结肠炎大鼠疼痛行为的初步证据。我们建议的独特特征包括这些靶点远离结肠炎部位，多学科方法，以及我们调查团队的多样化专业知识。

DESCRIPTION (provided by applicant): Pain originating from visceral organs such as stomach or intestine is an alarm of pathology, for example, pain associated with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. Despite recent advances in the treatment of colitis using systemic or local anti-inflammatory therapies, many patients still complain of intractable visceral pain. In a rat model of colitis, we propose to reverse signs of nociception at behavioral and neuronal levels by blocking novel cellular and molecular targets in the central nervous system. We hypothesize that, in rats with experimental colitis, immunogenic microglial cells in the spinal cord become activated and release pro-inflammatory mediators, which then enhance the excitability of visceral sensory neurons, leading to nociceptive behavior. We further hypothesize that activated microglia, but not other cell types of the spinal cord, selectively express the stress-activated protein p38 and adenosine triphosphate receptor P2X4, whereas blocking these signaling pathways attenuates neuronal hyperexcitability and behavioral signs of visceral nociception. These studies will help us begin to define sites for pharmacologic interventions that are remote (within the spinal cord) and distinct from the organ of initial pathology (the colon) to improve the analgesic potency of biologic therapies, while minimizing undesirable side effects. PUBLIC HEALTH RELEVANCE: Inflammation or injury to a visceral organ (an 'internal' organ like stomach or gut) is often associated with unpleasant visceral sensation of pain. Certain forms of visceral pain, such as that induced by colon inflammation, cannot be effectively managed. To ameliorate treatment options for intractable visceral pain, we show in this application preliminary evidence for successful reversal of pain behavior in rats with colitis by blocking novel cellular and molecular targets in the spinal cord. Unique features of our proposal include the remote location of these targets from the site of colon inflammation, the multidisciplinary approach, and the diversified expertise of our team of investigators.