William Clarke, Ph.D.

Research in our lab is focused on understanding the cellular and molecular mechanisms of drug efficacy (the ability of a drug to produce a response, following interaction with a receptor). Together with my long-time collaborator, Dr. Kelly Berg, our work has employed a combination of quantitative pharmacological, biochemical, molecular, cellular and behavioral approaches to understand how drugs activate G protein coupled receptors (GPCRs) to regulate cellular signaling and change behavior. We are especially interested in ligand-independent (constitutive) receptor activity, inverse agonism, and functional selectivity (also known as biased agonism - the ability of different ligands that act at the same receptor to produce different responses). We are also interested in how these pharmacological parameters differ with cell phenotype and cell physiological state. For the past several years our studies have centered upon the regulation and function of peripheral opioid receptors expressed by peripheral pain-sensing neurons and their role as potential targets for safer treatments for pain. Inhibition of these pain-sensing neurons can produce powerful analgesia (think local anesthetics). Opioid drugs that are modified to be peripherally-restricted so that they do not enter the CNS would be effective analgesics for some forms of pain (post-surgical, inflammatory, etc.) that involve activity of the peripheral pain-sensing neurons but would be devoid of the serious adverse effects that are due to opioid action on receptors expressed in the CNS (respiratory depression, addiction, abuse, sedation, etc.). We utilize a complementary system to study opioid receptor function and regulation in peripheral pain-sensing neurons that includes study of peripheral sensory neurons, derived from the trigeminal and dorsal root ganglia, in culture and well as in vivo in behavioral assays of pain. The combination of ex vivo (primary neuronal cultures) and in vivo studies is a powerful approach that allows for rigorous, quantitative, pharmacological analyses of cellular signaling systems and assessment of the physiological relevance of findings obtained from ex vivo studies.