Blood Brain Barrier Changes Induced by Pain

疼痛引起的血脑屏障变化

• 批准号: 7558233
• 负责人: THOMAS Paul DAVIS
• 金额: $ 65.69万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/7558233
• 关键词: Acute; Acute Pain; Address; Affect; Alzheimer' s Disease; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Applications Grants; Arthritis; Atherosclerosis; Biochemical; Blood - brain barrier anatomy; Brain; CCL2 gene; Carrageenan; Categories; Caveolins; Cell physiology; Central Nervous System Diseases; Chronic; Complex; Diabetes Mellitus; Discipline; Drug Delivery Systems; Drug usage; Endothelial Cells; Formalin; Freund' s Adjuvant; Functional disorder; Goals; Grant; Growth Factor; Herpes zoster disease; Hyperalgesia; Immune; Immune response; Immune system; In Situ; Inflammation; Inflammation Mediators; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-6; Intervention; Ischemic Stroke; Laboratories; Lead; Location; Mediating; Medical; Medicine; Methods; Modeling; Molecular; Molecular Weight; Monocyte Chemoattractant Protein-1; Multi-Drug Resistance; Multiple Sclerosis; Neuraxis; Neuroglia; Neurons; Opiates; P-Glycoprotein; P-Glycoproteins; Pain; Pathology; Pathway interactions; Perfusion; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Principal Investigator; Production; Productivity; Prostaglandin-Endoperoxide Synthase; Proteins; Rattus; Regulation; Relative (related person); Research; Research Project Grants; Rho-associated kinase; Role; Signal Transduction; Site; Specific qualifier value; Stimulus; Structure; Suggestion; TNF gene; Tight Junctions; Time; Transforming Growth Factors; Tumor Necrosis Factor-alpha; United States; United States National Institutes of Health; Western Blotting; Work; afferent nerve; claudin 3; clinically relevant; cost; cytokine; hypothalamic-pituitary-adrenal axis; in vivo; inflammatory marker; inflammatory pain; innovation; mRNA Expression; monocyte; new therapeutic target; novel therapeutics; occludin; programs; public health relevance; response; response to injury; rho; tool; trafficking; transmission process; uptake

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.

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