Differences in δ- and μ-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects

Blockade of brain μ-opioid receptor (μ-OR) and δ-opioid receptor (δ-OR) was investigated in recently abstinent alcohol-dependent subjects (N=21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-β-naltrexol. Regional brain μ-OR binding potential (BP) and δ-OR K_i was measured using [¹¹C]carfentanil (CAR) positron emission tomography (PET) and [¹¹C]methyl naltrindole ([¹¹C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [¹¹C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean+SD% inhibition=94.9+4.9%). Naltrexone only partially inhibited the [ ¹¹C]MeNTI K_i and there was more variability across subjects (mean+SD% inhibition=21.1+14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of δ-OR K_i in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of μ-OR BP. Peak levels of 6-β-naltrexol were not significantly correlated with % inhibition of μ-OR BP or δ-OR K _i. Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the μ-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of δ-OR and greater variability in δ-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in δ-OR blockade by naltrexone and clinical outcomes should be explored.