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An Opioid Agonist that Does Not Induce µ-Opioid Receptor—Arrestin Interactions or Receptor Internalization

Departments of Pharmacology and Psychiatry, the Ohio State University College of Medicine, Columbus, Ohio (L.M.B., C.E.G., R.A.M.); Division of Medicinal & Natural Products Chemistry, College of Pharmacy, the University of Iowa, Iowa City, Iowa (K.T., W.W.H., T.E.P.); and Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (R.B.R.)

G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different µ-opioid receptor (µOR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a µOR with low affinity for -arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both -arrestins and the receptors. Here, we evaluate µOR trafficking in response to activation by a novel µ-selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of -arrestin-2 to the µOR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced -arrestin interactions and µOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that -arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation, and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.

Address correspondence to: Dr. Laura M. Bohn, 333 W 10th Avenue, 5184A Graves Hall, Columbus, OH 43210. E-mail: laura.bohn{at}osumc.edu

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