MU-OPIOID RECEPTOR PHOSPHORYLATION, DESENSITIZATION, AND LIGAND EFFICACY

mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways: agonis t-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation (1), To better understand the nature of the agonist-induce d mu receptor phosphorylation events, we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic act ivities on mu receptor phosphorylation and desensitization, Exposure t o the potent full agonists sufentanil, dihydroetorphine, etorphine, et onitazine, and [D-Ala2, MePhe4, Glyol5]enkephalin (DAMGO) led to stron g receptor phosphorylation, while methadone, l-alpha-acetyl-methadone (LAAM), morphine, meperidine, DADL, beta-endorphin((1-31)), enkephalin s, and dynorphin A((1-17)) produced intermediate effects, The partial agonist buprenorphine minimally enhanced receptor phosphorylation whil e antagonists failed to alter phosphorylation, Buprenorphine and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO, The rank order of opiate ligand efficaci es in producing mu receptor-mediated functional desensitization genera lly paralleled their rank order of efficacies in producing receptor ph osphorylation, Interestingly, the desensitization and phosphorylation mediated by methadone and LAAM were disproportionate to their efficaci es in two distinct test systems, This generally good fit between the e fficacies of opiates in mu receptor activation, phosphorylation, and d esensitization supports the idea that activated receptor/agonist/G-pro tein complexes and/or receptor conformational changes induced by agoni sts are required for agonist-induced mu receptor phosphorylation, Data for methadone and LAAM suggest possible contribution from their enhan ced desensitizing abilities to their therapeutic efficacies.