mu Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine
by
Roth SH.
Selley DE, Cao CC, Sexton T, Schwegel JA, Martin TJ, Childers SR.
Department of Pharmacology and Toxicology,
Virginia Commonwealth University,
Medical College of Virginia, Box 980524,
1112 East Clay Street, Richmond,
VA 23298-0524, USA.
deselley@hsc.vcu.edu
Biochem Pharmacol. 2001 Aug 15;62(4):447-55.

ABSTRACT

The efficacy of heroin metabolites for the stimulation of mu opioid receptor-mediated G-protein activation was investigated using agonist-stimulated [(35)S]guanosine-5'-O-(gamma-thio)-triphosphate binding. In rat thalamic membranes, heroin and its primary metabolite, 6-monoacetylmorphine (6-MAM), were more efficacious than morphine or morphine-6-beta D-glucuronide. This increased efficacy was not due to increased action of heroin and 6-MAM at delta receptors, as determined by competitive antagonism by naloxone, lack of antagonism by naltrindole, and competitive partial antagonism with morphine. In agreement with this interpretation, the same relative efficacy profile 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 receptor-mediated G-protein activation. The activity of heroin was attributed to in vitro deacetylation to 6-MAM, as confirmed by HPLC analysis. These results indicate that the heroin metabolite 6-MAM possesses higher efficacy than other heroin metabolites at mu opioid receptors, which may contribute to the higher efficacy of heroin compared with morphine in certain behavioral paradigms in vivo.

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Hydromorphone
Opioid receptors
Mu opioid receptor subtypes
High 6-MAM levels in heroin users
The heroin-specific metabolite 6-MAM

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