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There is confusion in the literature concerning the relative agonist efficacy of methadone at μ-opioid receptors (MOPrs). Here, we confirm that methadone is a full agonist in guanosine 5′-O-[gamma-thio]triphosphate (GTPγS) binding studies. Methadone, however, seems to have low efficacy in studies of MOPr activation of G-protein-gated potassium (GIRK) channels, but this is because it directly inhibits the GIRK channels. Methadone also inhibits α2-adrenoceptor-activated GIRK channels. Methadone is not a specific GIRK channel blocker. It also inhibits small conductance Ca2+-activated K+ (SK2) channels. We conclude that methadone is a full agonist at MOPrs that, as we and others have shown, induces MOPr desensitization and internalization.