mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine

The efficacy of heroin metabolites for the stimulation of CL opioid recepto r-mediated G-protein activation was investigated using agonist-stimulated [ S-35]guanosine-5 ' -O-(gamma -thio)-triphosphate binding. In rat thalamic m embranes, heroin and its primary metabolite, 6-monoacetylmorphine (6-MAM), were more efficacious than morphine or morphine-6-betaD-glucuronide. This i ncreased efficacy was not due to increased action of heroin and 6-MAM at de lta receptors, as determined by competitive antagonism by naloxone, lack of antagonism by naltrindole, and competitive partial antagonism with morphin e. In agreement with this interpretation. the same relative efficacy profil e of heroin and its metabolites was observed at the cloned human mu opioid receptor expressed in C6 glioma cells. Moreover, these efficacy differences were GDP-dependent in a manner consistent with accepted mechanisms of rece ptor-mediated G-protein activation. The activity of heroin was attributed t o in vitro deacetylation to 6-MAM, as confirmed by HPLC analysis. These res ults indicate that the heroin metabolite 6-MAM possesses higher efficacy th an other heroin metabolites at CL opioid receptors, which may contribute to the higher efficacy of heroin compared with morphine in certain behavioral paradigms in vivo. (C) 2001 Elsevier Science Inc. All rights reserved.