An opioid agonist that does not induce μ-opioid receptor -: Arrestin interactions or receptor internalization

G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different mu-opioid receptor ( mu OR) 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 mu OR with low affinity for beta-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors. Here, we evaluate mu OR trafficking in response to activation by a novel mu-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 mu-arrestin-2 to the mu OR and does not lead to receptor internalization. Moreover, whereas G protein- coupled receptor kinase overexpression can promote morphine- induced beta-arrestin interactions and mu OR internalization, such manipulations do not promote herkinorin- induced trafficking. Studies in mice have shown that mu- 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.