Mu opioid receptor activation without arrestin‐interactions; a pharmacological approach.

G protein coupled receptors, including the opioid receptors, can be regulated by phosphorylation and the subsequent binding of beta‐arrestins (Barrestins). Such regulation has substantial impacts on behavioral responsiveness to drugs such as the opioid analgesic, morphine. Extensive studies in Barrestin2‐KO mice have shown that, in the absence of Barrestin2, morphine produces more antinociception, less antinociceptive tolerance and less side effects, including constipation and respiratory suppression. A new class of opioid agonists have recently been derived from the hallucinogenic mint, Salvia divinorum . Here we report on a chemical derivative of salvinorin A, termed Herkinorin, and its derivatives, that have high affinity for the mu opioid receptors, activate G protein coupling, activate MAP kinase cascades, yet do not recruit arrestins nor induce receptor internalization. Unlike morphine, which induces very little receptor internalization, the overexpression of the GPCR kinase, GRK2, does not allow for herkinorin‐induced receptor trafficking. Our most recent work demonstrates that herkinorin and its derivatives produce antinociception in vivo. We anticipate that opioid receptor agonists that do not promote Barrestin‐receptor interactions may produce similar physiological effects as those observed in the Barrestin2‐KO mice. Support: DA14600, DA18860 (L.M.B); DA18151 (T.E.P).