Blood Brain Barrier Changes Induced by Pain

疼痛引起的血脑屏障变化

基本信息

批准号：
7649767
负责人：
THOMAS Paul DAVIS
金额：
$ 5.27万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-05 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649767
关键词：
Acute Pain Adjuvant Affect Alzheimer&apos s Disease American Animals Anti-Inflammatory Agents Anti-inflammatory Appendix Applications Grants Arthritis Atherosclerosis Biochemical Blood - brain barrier anatomy Brain Carrageenan Categories Cell Fractionation Central Nervous System Diseases Chronic Complex Confocal Microscopy Density Gradient Centrifugation Diabetes Mellitus Drug Delivery Systems Drug usage Electron Microscopy Endothelial Cells Formalin Freund&apos s Adjuvant Functional disorder Goals Grant Growth Factor Herpes zoster disease Hyperalgesia Immune Immune response Immune system Immunoprecipitation In Situ Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interleukin-1 Interleukin-6 Intervention Ischemic Stroke Laboratories Lead Location Mediating Mediator of activation protein Medical Messenger RNA Methods Modeling Molecular Molecular Weight Multi-Drug Resistance Multiple Sclerosis Neuraxis Neuroglia Opiates P-Glycoprotein P-Glycoproteins Pain Pathology Pathway interactions Perfusion Peripheral Permeability Pharmaceutical Preparations Pharmacologic Substance Production Productivity Prostaglandin-Endoperoxide Synthase Proteins Public Health Range Rattus Relative (related person)Research Signal Transduction Site Stimulus Structure TNF gene Tight Junctions Time Transforming Growth Factors Tumor Necrosis Factor-alpha Two-Dimensional Gel Electrophoresis United States United States National Institutes of Health Western Blotting Work afferent nerve claudin 3 clinically relevant cost crosslink cyclooxygenase 1 cyclooxygenase 2 cytokine hypothalamic-pituitary-adrenal axis in vivo inflammatory pain innovation intracellular protein transport mRNA Expression novel therapeutics occludin protein expression protein localization location protein transport receptor response response to injury therapeutic target trafficking transmission process uptake

项目摘要

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.

描述（由申请人提供）：每年疼痛遭受超过8500万人的痛苦，造成巨大的痛苦和损失数十亿美元的药物治疗和生产力失去。疼痛诱导的血脑屏障（BBB）功能障碍显着改变了用于治疗疼痛的临床相关药物的大脑。此外，BBB功能障碍引发和/或加剧了许多中枢神经系统（CNS）以及与疼痛和/或炎症相关的非CNS疾病和病理学，包括阿尔茨海默氏病，缺血性中风，关节炎，关节炎，糖尿病，糖尿病，多发性硬化症和动脉粥样硬化。不幸的是，大多数关于神经药物在中枢神经系统中分布的研究是使用幼稚的，健康的动物进行的，而不是疼痛和/或炎症。我们实验室的研究表明，福音或完整弗朗德辅助引起的外周炎性疼痛增加了副细胞BBB渗透性，改变了耐多药（MDR）P-糖蛋白（P-GP）（P-GP）的表达，并在临床上使用了胶片的大脑治疗疼痛。此外，我们发现周围炎症性疼痛改变了关键紧密连接（TJ）蛋白质的表达和定位，Claudin-3，Claudin-5和Zona occludens 1（ZO-1）在限制BBB细胞细胞运输方面至关重要。所有类别的疼痛（急性，亚基和慢性）都可以通过疼痛的刺激或毒气引起，从而引起周围的先天免疫反应和CNS介导的反应。外围先天免疫反应涉及炎症部位的炎症介质的快速生产和局部释放。中枢神经系统对周围炎症疼痛的反应涉及神经胶质激活，促炎细胞因子和生长因子的从头合成以及夸张的疼痛传播（Hyperalgesia）。该提案的总体目标是详细了解周围疼痛和炎症如何导致BBB结构和功能的变化，从而导致对治疗疼痛和中枢神经系统疾病的重要药物的大脑递送的变化。我们的假设是，周围的先天免疫反应和CNS介导的对周围炎症性疼痛的反应引起了BBB微血管内皮细胞中关键TJ和MDR（P-GP）蛋白的表达和细胞内运输的变化，以及这些严重影响BBB细胞信号传导，细胞细胞通透性和外排运输。该赠款的目的将通过在我们的实验室中建立和工作的生化，分子，药理学和体内方法的结合来研究。该建议将阐明疼痛和炎症引起的BBB变化的潜在机制，并促进发现新型治疗靶标，以治疗BBB功能障碍和疼痛。公共卫生相关性：每年在美国遭受超过8500万人的疼痛，造成巨大的痛苦和损失数十亿美元的医疗治疗和生产力失去。疼痛引起的血脑屏障（BBB）功能障碍显着改变了用于治疗疼痛的临床重要药物的大脑。这项NIH赠款提案将研究由疼痛和炎症引起的BBB变化的关键机制，对于帮助发现用于治疗BBB功能障碍和疼痛的新治疗药物至关重要。