Blood Brain Barrier Changes Induced by Pain

描述(申请人提供)：在美国，疼痛每年折磨着8500多万人，造成巨大的痛苦，并造成数十亿美元的医疗费用和生产力损失。疼痛引起的血脑屏障(BBB)功能障碍显著改变了用于治疗疼痛的临床相关药物的脑内转运。此外，血脑屏障功能障碍会引发和/或加重许多中枢神经系统(CNS)和非中枢神经系统疾病，以及与疼痛和/或炎症相关的病理，包括阿尔茨海默病、缺血性中风、关节炎、糖尿病、多发性硬化症和动脉粥样硬化。不幸的是，大多数关于中枢神经系统药物分布的研究都是使用天真的、健康的、没有疼痛和/或炎症的动物进行的。本实验室的研究表明，角叉菜胶、福尔马林或完全弗氏佐剂诱导的外周炎性疼痛，增加了细胞旁血脑屏障通透性，改变了多药耐药(MDR)P-糖蛋白(P-gp)的表达，并改变了临床上用于治疗疼痛的阿片类药物的脑摄取。此外，我们发现，外周炎性疼痛改变了关键紧密连接(TJ)蛋白occludin、claudin-3、claudin-5和zona occludens 1(ZO-1)的表达和定位，这些蛋白在限制BBB细胞旁运输方面至关重要。所有类别的疼痛(急性、亚慢性和慢性)都可以由痛苦的刺激或炎症引起，这些刺激或炎症既能引起外周先天免疫反应，也能引起中枢神经系统介导的反应。外周先天免疫反应涉及炎症损伤部位炎症介质的快速产生和局部释放。中枢神经系统对外周炎性疼痛的反应包括神经胶质细胞的激活，促炎细胞因子和生长因子的从头合成，以及过度的疼痛传递(痛觉过敏)。这项提案的总体目标是详细了解外周疼痛和炎症如何导致血脑屏障结构和功能的变化，从而导致用于治疗疼痛和中枢神经系统疾病的重要药物向大脑的输送发生变化。我们的假设是，外周先天免疫反应和中枢神经系统对外周炎性疼痛的反应都会引起血脑屏障微血管内皮细胞中关键的TJ和MDR(P-gp)蛋白的表达和细胞内转运的变化，这些变化对血脑屏障细胞的信号转导、细胞旁通透性和外排运输都有重要影响。这笔赠款的目的将使用在我们实验室建立和工作的生化、分子、药理学和活体方法的组合进行研究。这一建议将阐明疼痛和炎症引起的血脑屏障改变的潜在机制，并将有助于发现治疗血脑屏障功能障碍和疼痛的新靶点。与公共卫生相关：在美国，每年有8500多万人遭受疼痛的折磨，造成巨大的痛苦，并造成数十亿美元的医疗成本和生产力损失。疼痛引起的血脑屏障(BBB)功能障碍显著改变了临床上用于治疗疼痛的重要药物的脑内输送。NIH的这项拨款提案将研究疼痛和炎症引起的血脑屏障改变的关键机制，并将在帮助发现治疗血脑屏障功能障碍和疼痛的新治疗药物方面发挥关键作用。

DESCRIPTION (provided by applicant): Pain afflicts more than 85 million people in the United States each year, causing tremendous suffering and costing billions of dollars in medical treatments and lost productivity. Pain-induced blood-brain barrier (BBB) dysfunction significantly alters transport into the brain of clinically relevant drugs used to treat pain. Moreover, BBB dysfunction initiates and/or exacerbates numerous central nervous system (CNS) and non-CNS diseases and pathologies associated with pain and/or inflammation, including Alzheimer's disease, ischemic stroke, arthritis, diabetes, multiple sclerosis and atherosclerosis. Unfortunately, most research on the distribution of neuropharmaceuticals to the CNS has been performed using naive, healthy animals not suffering from pain and/or inflammation. Studies from our laboratory show that peripheral inflammatory pain induced by ?-carrageenan, formalin or complete Freund's adjuvant, increases paracellular BBB permeability, alters multi-drug resistant (MDR) P-glycoprotein (P-gp) expression and brain uptake of opiates used clinically to treat pain. Additionally, we find that peripheral inflammatory pain alters expression and localization of the key Tight Junction (TJ) proteins occludin, claudin-3, claudin-5 and zona occludens 1 (ZO-1) which are critically important in restricting BBB paracellular transport. All categories of pain (acute, subchronic and chronic) can be initiated by a painful stimulus or inflamagen that elicits both a peripheral innate immune response and a CNS-mediated response. The peripheral innate immune response involves the rapid production and local release of inflammatory mediators at the site of injury of inflammation. The CNS response to peripheral inflammation pain involves glia activation, de novo synthesis of proinflammatory cytokines and growth factors, and exaggerated pain transmission (hyperalgesia). The overall goal of this proposal is to provide a detailed understanding of how peripheral pain and inflammation cause the changes in BBB structure and function that lead to altered delivery to the brain of important pharmaceuticals used to treat pain and CNS disease. Our hypothesis is that both the peripheral innate immune response and the CNS-mediated response to peripheral inflammatory pain elicit changes in the expression and intracellular trafficking of key TJ and MDR (P-gp) proteins in microvascular endothelial cells at the BBB, and that these changes critically affect BBB cell signaling, paracellular permeability and efflux transport. The aims of this grant will be investigated using a combination of biochemical, molecular, pharmacological and in vivo methods established and working in our laboratory. This proposal will elucidate underlying mechanism of BBB changes induced by pain and inflammation, and will facilitate discovery of novel therapeutic targets for treating both BBB dysfunction and pain. PUBLIC HEALTH RELEVANCE: Pain afflicts more than 85 million people in the United States each year, causing tremendous suffering and costing billions of dollars in medical treatments and lost productivity. Pain-induced blood-brain barrier (BBB) dysfunction significantly alters delivery into the brain of clinically important drugs used to treat pain. This NIH grant proposal will study key mechanisms of BBB changes induced by pain and inflammation, and will be critical in aiding the discovery of new therapeutic drugs for treating BBB dysfunction and pain.