RT Journal Article
SR Electronic
T1 An Opioid Agonist that Does Not Induce μ-Opioid Receptor—Arrestin Interactions or Receptor Internalization
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 549
OP 557
DO 10.1124/mol.106.028258
VO 71
IS 2
A1 Groer, C. E.
A1 Tidgewell, K.
A1 Moyer, R. A.
A1 Harding, W. W.
A1 Rothman, R. B.
A1 Prisinzano, T. E.
A1 Bohn, L. M.
YR 2007
UL http://molpharm.aspetjournals.org/content/71/2/549.abstract
AB 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 β-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both β-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 β-arrestin-2 to the μOR and does not lead to receptor internalization. Moreover, whereas G protein-coupled receptor kinase overexpression can promote morphine-induced β-arrestin interactions and μOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that β-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. The American Society for Pharmacology and Experimental Therapeutics