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Received for publication June 23, 2006.
Revised October 31, 2006.
Accepted for publication November 6, 2006.
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(µOR) ligands can lead to varying degrees of receptor regulation presumably due to 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 mu-selective agonist derived from the naturally occurring plant product, salvinorin A. Interestingly, this compound, termed herkinorin, does not promote the recruitment of -arrestin-2 to the µOR and does not lead to receptor internalization. Moreover, while GRK 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.
Key words:
Opioid, Receptor synthesis/trafficking, Desensitization/uncoupling, Sequestration/Internalization, GRKs, barrestins, Phosphorylation/Dephosphorylation, MAP Kinase, Opioids
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