BLOOD BRAIN BARRIER CHANGES INDUCED BY PAIN

疼痛引起的血脑屏障变化

• 批准号: 7081279
• 负责人: THOMAS Paul DAVIS
• 金额: $ 35.14万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081279
• 关键词: analgesics; biological signal transduction; biological transport; blood brain barrier; chronic pain; cytokine; disease /disorder etiology; endogenous opioid; high performance liquid chromatography; hormones; immune system; inhibitor /antagonist; laboratory rat; molecular biology; nervous system; pain; perfusion; pharmacology; phosphorylation; physiology; stimulant /agonist; stimulus /response; tight junctions; transport proteins

DESCRIPTION (provided by applicant): Chronic pain affects nearly 70 million people a year in the United States and costs billions of dollars in medical treatment and lost productivity. To date, all investigations concerning the blood-brain barrier (BBB) and the delivery of analgesics have been performed in naive non-pained animals. It is becoming increasingly clear that the blood-brain barrier is not a static barrier but can be modulated by a number of factors from the immune, neuronal and hormonal systems. During pain all three of these systems are activated. The hypothesis of this study is that pain activates the immune, neuronal and hormonal systems leading to an alteration in the molecular and functional properties in the blood-brain barrier. This alteration will lead to a change in the transport of substances across the blood-brain barrier and may have a role in the etiology of chronic pain. In preliminary studies, we have seen an increase in the permeability of the rat blood-brain barrier during three models of peripheral pain (Formalin, A-carrageenan, Complete Freunds Adjuvant) to [S14C] Sucrose which will only cross the blood-brain barrier if the tight junctions have been compromised. In parallel Western blot studies we observed a reduction in occiudin (an integral BBB tight junction protein) and an increase in ZO-1 and actin (an accessory and cytoskeletal protein respectively). This indicates that the pain has altered BBB tight junctions. ELISA and ribonuclease protection assays, show that levels of TNF-a in peripheral blood and TNF-a, IFN-gamma, and interleukins 5 and 6 are altered in the CNS in a time dependent manner during A-carrageenan induced pain. All of these substances have previously been shown to alter tight junction proteins. Therefore, this proposal is designed to further investigate the changes induced by pain and the mechanisms that promote these changes by utilizing the tools of physiology, molecular biology and pharmacology in an integrative manner. It is our long-term aim to identify pharmacological agents that can treat these alterations in the blood-brain barrier.

描述（由申请人提供）：慢性疼痛每年在美国影响近7000万人，造成数十亿美元的医疗和生产力损失。迄今为止，有关血脑屏障（BBB）的所有研究和镇痛药的递送均已在幼稚的非受污染动物中进行。越来越清楚的是，血脑屏障不是静态障碍，而是可以通过免疫，神经元和激素系统的许多因素来调节。 在疼痛期间，所有这三个系统都被激活。这项研究的假设是，疼痛激活了免疫，神经元和激素系统，导致血脑屏障中分子和功能特性的改变。这种改变将导致物质在血脑屏障中的运输发生变化，并可能在慢性疼痛的病因中起作用。 在初步研究中，在三种模型的外周疼痛模型（福尔马林，A-Carrageenan，完整的Freunds佐剂）中，我们发现大鼠血脑屏障的渗透性增加了[S14C]蔗糖，只有在紧密的连接处被置于侵犯时，这些蔗糖只会越过血脑屏障。在平行的蛋白质印迹研究中，我们观察到OCCIUDIN（积分BBB紧密连接蛋白）的降低以及ZO-1和肌动蛋白（分别是辅助和细胞骨架蛋白）的增加。这表明疼痛改变了BBB紧密连接。 ELISA和核糖核酸酶保护分析表明，外周血和TNF-A，IFN-GAMMA和白介碱5和白介素5和6个tnf-A的水平在A-carrageenan诱导的疼痛中以时间依赖的方式改变了中枢神经系统。所有这些物质先前已显示出改变紧密的连接蛋白。因此，该建议旨在进一步研究疼痛引起的变化以及通过以整合方式利用生理学，分子生物学和药理学工具来促进这些变化的机制。我们的长期目标是确定可以治疗血脑屏障中这些改变的药理学剂。