Methadone: does it really have low efficacy at micro-opioid receptors?
There is confusion in the literature concerning the relative agonist efficacy of methadone at micro-opioid receptors (MOPrs). Here, we confirm that methadone is a full agonist in guanosine 5'-O-[gamma-thio]triphosphate (GTPgammaS) 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 alpha2-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
Ivan
I
Department of Physiology and Pharmacology, University of Bristol, Bristol, UK.
Braksator
Ellen
E
Bailey
Chris P
CP
Goodchild
Sam
S
Marrion
Neil V
NV
Kelly
Eamonn
E
Henderson
Graeme
G
D000818:Animals; D000831:Animals, Newborn; D002461:Cell Line, Transformed; D004347:Drug Interactions; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008691:Methadone / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D014162:Transfection
D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D008691:Methadone