About the Davis Lab
Our laboratory continues its long-term biodistribution/ pharmacokinetics research program, continuously funded by N.I.H. since 1981, by studying mechanisms involved in delivering drugs across the blood-brain barrier (BBB) to the central nervous system (CNS) in pathological disease states. We have recently discovered that specific drug transporters are affected by various pathologies and, therefore, can be targeted to enhance delivery. We are also actively studying the effect of pathologies such as peripheral inflammatory pain and hypoxia/reoxygenation stress on paracellular permeability and tight junction protein organization at the BBB. We have recently shown that short-term hypoxic stress leads to significant alterations in BBB permeability that can be reversed by Tempol, a free radical scavenger, suggesting that oxidative stress plays a critical role in altering BBB functional integrity, at the level of tight junction proteins, during pathophysiological insult. This work has significant consequences to the study of stroke. Additionally, we have shown that peripheral inflammatory pain has significant effects on BBB structure and function characterized by changes in oligomeric assemblies of the key tight junction proteins occludin and claudin-5, and altered functional expression and trafficking of the drug efflux transporter P-glycoprotein. These changes in BBB functional integrity lead to variations in delivery of opioid analgesic drugs such as codeine and morphine, to the CNS. Furthermore, we have demonstrated that changes in BBB functional integrity during peripheral inflammatory pain are regulated, in part, by altered transforming growth factor-beta (TGF-β) signaling at the level of the brain microvascular endothelium. We are now in the exciting position of coupling our program in analgesic biodistribution with our program in neuropathology.