Neutral antagonist activity of naltrexone and 6β‐naltrexol in naïve and opioid‐dependent C6 cells expressing a µ‐opioid receptor

摘要: BACKGROUND AND PURPOSE Adenylyl cyclase sensitization occurs on chronic agonist activation of mu-opioid receptors and is manifested by an increase in cAMP levels (overshoot) challenge with antagonist. It has been proposed that a long lasting constitutively active receptor formed exposure antagonists inverse activity rapidly return the to basal state causing overshoot more severe withdrawal response vivo. This hypothesis depends accurate characterization neutral properties opioid antagonists. EXPERIMENTAL APPROACH C6 glioma HEK293 cells expressing were used. Opioid examined for their ability induce following treatment DAMGO ([D-Ala(2),N-Me-Phe(4),Glyol(5)]-enkephalin). The compounds also characterized as agonists, agonists or using assays competitive binding, [(35)S]GTPgammaS (guanosine-5'-O-(3-[(35)S]thio)triphosphate) binding changes cell surface expression. KEY RESULTS Naltrexone, 6beta-naltrexol naloxone indistinguishable opioid-naive dependent acted delta-opioid RTI-5989-25 [(+)-N-[trans-4'-(2-methylphenyl)-2'-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine], 3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine, was at receptor, peptide antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) showed variable, assay-dependent properties. All precipitated same degree opioid-dependent cells. CONCLUSIONS IMPLICATIONS Antagonists may be show activity. Formation not requirement development expression adenylyl sensitization.