Research Spotlight
Kelly Standifer, Ph.D.
Dr. Kelly Standifer joined the College of Pharmacy as Professor of Pharmaceutical Sciences. Her research interests, ultimately, is to develop alternative therapeutic options (to morphine) for the treatment of severe pain. The newest member of the opioid receptor family, opioid receptor like-1 receptor (ORL1), and its endogenous agonist, orphanin FQ/nociceptin (OFQ/N), have been strongly implicated in the development of morphine tolerance. Chronic morphine treatment increases levels of OFQ/N; blocking the actions of OFQ/N significantly reduce the extent to which the analgesic actions of morphine are reduced. Using human neuronal cell lines that natively express mu and ORL1 receptors, we study the cellular mechanisms of ORL1 and mu opioid receptor activation (by the endogenous peptides OFQ/N and Dynorphin, and the synthetic agonists, DAMGO and morphine), and the cellular mechanisms of ORL1- and mu opioid receptor-mediated mu and ORL1 tolerance and cross-tolerance. Acutely, OFQ/N activates protein kinase C (PKC), which activates and translocates G protein-coupled receptor kinase 2 (GRK2) and GRK3 to the cell membrane where GRK2 can quickly desensitize the mu opioid receptor in the presence of a mu opioid agonist such as morphine. Our next step is to determine where these changes occur in vivo, and how they might be manipulated to reduce the extent of morphine tolerance development.
ORL1 desensitization is produced by GRK3. Tolerance induced by prolonged exposure to OFQ/N and/or morphine treatment also involves GRK. Similar to morphine, prolonged OFQ/N treatment (24 h or more) upregulates GRK levels. Ultimately, though, it is the increased availability of GRK that produces the rapid tolerance and/or cross-tolerance upon challenge with an agonist. We are in the process of studying ORL1 phosphorylation sites, and how mutation of these sites affects receptor function.
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