Blood-to-CNS Drug Uptake in Pain/Rheumatoid Arthritis

描述（由申请人提供）：风湿性关节炎（RA）是一种慢性疾病，影响200万至300万美国人，女性的患病率是男性的三倍。虽然RA通常发生在20至50岁的人群中，但儿童和老年人也可能患上RA。每年，650亿美元用于患有肌肉骨骼疾病（如RA）的患者的医疗费用，收入损失和生产力损失。关节痛（AP）是类风湿关节炎的主要症状。 迄今为止，CNS药物穿过血脑屏障（BBB）摄取的研究已经在幼稚（即，非患病）动物，尽管研究已经表明中枢和外周炎症调节BBB功能（即，通透性）和内皮细胞细胞结构。拟议的研究将融合我们实验室已经存在的两个专业领域：药物输送到中枢神经系统和评估血脑屏障的生化和分子改变。本提案的目的是研究AP（使用急性关节炎疼痛大鼠模型）与RA（使用慢性RA大鼠模型）对CNS药物摄取的影响（即，BBB通透性）和内皮细胞结构，并最终区分AP和RA对阿片类镇痛剂CNS递送的影响。此外，将评估RA（一种涉及关节的慢性疾病状态）对用于治疗RA本身的药物的CNS摄取的影响。这些研究具有临床相关性，因为疾病相关的BBB渗透性增加可能是患者接受阿片类药物和RA药物给药后有时观察到的CNS毒性的一个因素。 我们的假设是，物质（包括阿片类镇痛药和RA药物）转运到大脑中的功能变化将发生由于在AP和RA期间释放疼痛/疾病介质引起的BBB的生物化学和分子结构的改变。这项研究将使我们能够区分急性关节疼痛（AP）对BBB的影响和慢性疾病（RA）对BBB的影响，在药物递送和递送改变的机制方面。

DESCRIPTION (provided by applicant): RHEUMATOID ARTHRITIS (RA) is a chronic disease that affects two to three million Americans and is three times more prevalent in women than in men. While RA typically occurs in people twenty to fifty years old, children and the elderly can also develop RA. Every year, $65 billion is spent on medical costs, lost income, and lost productivity for patients suffering from musculoskeletal conditions such as RA. ARTHRITIC PAIN (AP) is a dominant symptom of RA. To date, studies of CNS drug uptake across the blood-brain barrier (BBB) have been carried out in naive (i.e., nondiseased) animals, despite the fact that studies have shown that central and peripheral inflammation modulates BBB function (i.e., permeability) and endothelial cell cytoarchitecture. The proposed studies will meld two areas of expertise already present in our laboratory: drug delivery to the CNS and assessment of biochemical and molecular alterations of the blood-brain barrier. The goal of this proposal is to investigate the effects of AP (using an acute arthritis pain rat model) versus RA (using a chronic RA rat model) on CNS drug uptake (i.e., BBB permeability) and endothelial cell structure and to ultimately differentiate between the effects of AP and RA on CNS delivery of opioid analgesics. Additionally, the influence of RA (a chronic disease state involving the joints) on CNS uptake of drugs used to treat RA itself will be assessed. These studies are clinically relevant since disease-associated BBB permeability increases could be a factor in the CNS toxicity sometimes observed following administration of opioids and RA drugs to patients. Our hypothesis is that functional changes in the transport of substances (including opioid analgesics and RA drugs) into the brain will occur due to alterations in the biochemical and molecular structure of the BBB caused by the release of pain/disease mediators during AP and RA. This study will allow us to differentiate between acute joint pain (AP) effects on the BBB and chronic disease (RA) effects on the BBB in terms of drug delivery and the mechanisms by which delivery is altered.