We study different aspects of opioid peptide functioning in the nervous system. Endogenous opioids are released during stress to regulate nociception (pain), emotional state (euphoria, dysphoria, depression), and craving for addictive drugs (cocaine, opiates). We are asking how these complex behavioral effects are encoded by molecular, cellular and systems level events. At the molecular level, we study signal transduction events following opioid receptor activation using protein phosphorylation assays, specific antagonists and agonists, and transgenic mice having specific gene deletions and over-expressions. At the cellular level, we use confocal microscopy and electrophysiological assays to define the mechanisms of opioid effects on excitability. At the systems level, we use immunohistochemical analysis of changes in regional morphology, gene expression and protein phosphorylation to define the responsive neural circuits. At the behavioral level, we measure changes caused by opioid peptide release that mediate the stress response and potentiate the addictive properties of cocaine and opiates.
An example of the kind of results recently obtained include studies showing that chronic stress (repeated forced swim, repeated social defeat, chronic neuropathic pain, acute footshock) induces the release of endogenous dynorphin opioids that activate kappa opioid receptors and MAPK pathways which potentiate rewarding effects of cocaine and that induce relapse of drug seeking behavior. We are defining the sites in the brain where these effects occur, the intracellular signaling mechanisms responsible, and the electrophysiological effects in the local neuronal circuit underlying the behavioral responses. Our simple hypothesis is that dynorphin encodes the dysphoric effects of stressful experience that increase the motivation for euphoric/addictive drugs. Understanding the molecular and cellular mechanisms of these actions has therapeutic implications for the treatment of addiction.
Copyright © 2003-2013 Molecular & Cellular Biology Program, University of Washington
Fred Hutchison Cancer Research Center | University of Washington
Institute for Systems Biology | Seattle Biomed