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

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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.