Diverse Kappa Opioid Receptor Agonists: Relationships Between Signaling and Behavior

The opioid system, comprised mainly of the three opioid receptors (kappa, mu and delta) and their endogenous neuropeptide ligands (dynorphin, endorphin and enkephalin, respectively), mediates mood and reward. Activation of the mu opioid receptor is associated with positive reward and euphoria, while activation of the kappa opioid receptor (KOR) has the opposite effect. Activation of the KOR causes a decrease in dopamine levels in reward-related regions of the brain, and can block the rewarding effects of various drugs of abuse, making it a potential drug target for addictive diseases. KOR agonists are of particular interest for the treatment of cocaine and other psychostimulant addictions, because there are currently no available medications for these diseases. Studies in humans and animals, however, have shown that activation of the KOR also causes negative side effects such as hallucinations, aversion and sedation. Several strategies are currently being employed to develop KOR agonists that block the rewarding effects of drugs of abuse with fewer side effects, including KOR agonists with unique pharmacology. The goal of the research presented here was to profile the signaling pathways activated by KOR agonists and to investigate relationships between unique pharmacology and animal models of KOR-mediated behaviors, in order to better understand how to target the KOR for therapeutic use