There is confusion in the literature concerning the relative agonist efficacy of methadone at mu-opioid receptors (MOPrs). Here, we confirm that methadone is a full agonist in guanosine 5'-O-[gamma-thio]triphosphate (GTP gamma S) 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 alpha(2)-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.
Rodriguez-Martin, I., Braksator, E., Bailey, C. P., Goodchild, S., Marrion, N. V., Kelly, E., & Henderson, G. (2008). Methadone: Does it really have low efficacy at mu-opioid receptors? Neuroreport, 19(5), 589-593. https://doi.org/10.1097/WNR.0b013e3282f97b64