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

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性疾病，影响着200万至300万美国人，女性的发病率是男性的三倍。虽然类风湿性关节炎通常发生在20至50岁的人群中，但儿童和老年人也可能患上类风湿性关节炎。每年，有650亿美元花在患有类风湿性关节炎等肌肉骨骼疾病的患者的医疗费用、收入损失和生产力损失上。关节炎痛(AP)是RA的主要症状。 迄今为止，尽管研究表明中枢和外周炎症调节血脑屏障的功能(即通透性)和内皮细胞的细胞结构，但对中枢神经系统药物跨血脑屏障(BBB)摄取的研究仍在幼稚(即未患病)动物身上进行。拟议的研究将融合我们实验室现有的两个专业领域：向中枢神经系统提供药物，以及评估血脑屏障的生化和分子变化。该方案的目的是观察AP(使用急性关节炎疼痛大鼠模型)和RA(使用慢性RA大鼠模型)对中枢药物摄取(即血脑屏障通透性)和内皮细胞结构的影响，并最终区分AP和RA对中枢阿片类镇痛剂输送的影响。此外，还将评估RA(一种涉及关节的慢性病状态)对用于治疗RA本身的药物的中枢神经系统摄取的影响。这些研究具有临床意义，因为疾病相关的血脑屏障通透性增加可能是患者服用阿片类药物和RA药物后有时观察到的中枢神经系统毒性的一个因素。 我们的假设是，在AP和RA期间，由于疼痛/疾病介质的释放导致血脑屏障的生化和分子结构的改变，物质(包括阿片类镇痛剂和RA药物)进入大脑的功能将发生变化。这项研究将使我们能够区分急性关节疼痛(AP)对血脑屏障的影响和慢性疾病(RA)对血脑屏障的影响在药物传递方面以及改变传递的机制方面。

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.