Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Abstract

Blockade of brain m-opioid receptor (m-OR) and d-opioid receptor (d-OR) was investigated in recently abstinent alcohol-dependent subjects (N ¼ 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-b-naltrexol. Regional brain m-OR binding potential (BP) and d-OR K i was measured using [ 11 C]carfentanil (CAR) positron emission tomography (PET) and [11 C]methyl naltrindole ([ 11 C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [ 11 C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean + SD% inhibition ¼ 94.9 + 4.9%). Naltrexone only partially inhibited the [ 11 C]MeNTI K i and there was more variability across subjects (mean + SD% inhibition ¼ 21.1 + 14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of d-OR K i in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of m-OR BP. Peak levels of 6-b-naltrexol were not significantly correlated with % inhibition of m-OR BP or d-OR K i . Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the m-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of d-OR and greater variability in d-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 d-OR blockade by naltrexone and clinical outcomes should be explored.

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study

“…The potential efficacy of NTX, an opioid antagonist with greatest affinity for the μ-opioid receptor and to a lesser but meaningful extent κ-and δ-opioid receptors (Lee et al, 1988;Weerts et al, 2008), for the treatment of drug use disorders beyond alcoholism and opioid dependence may lie on a common mechanism of drug effects involving the activation of the endogenous opioid system (Herz, 1997;Kreek, 1996). Acute oral amphetamine administration has been shown to induce endogenous opioid release in many brain regions frequently implicated in addiction, including the basal ganglia, frontal cortex areas, thalamus, and striatum (Colasanti et al, 2012;Mick et al, 2014).…”

Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials

“…Naltrexone has low affinity at κ receptors in the brain and spinal cord and little to no activity at δ receptors in the spinal cord and peripheral nervous system [27]. Actually, pharmacological studies, established that 95% of cerebral µ receptors are occupied after an oral dose of 50 mg while only partial inhibition is produced on δ receptors [28]. As higher doses than 50 mg per day are needed to produce inhibition of δ receptors [28], we could speculate that these receptors can play a critical role in naltrexone effect in broadly defined behavioral addictions treatment.…”

δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

“…Naltrexone's therapeutic effects on drinking have been proposed to be mediated through the MOR (Ghozland et al, 2005;Weerts et al, 2008), and blocking opioid signaling in the VTA diminishes EtOH reinforcement (Bechtholt and Cunningham, 2005). To evaluate the role of VTA MORs in drinking and to compare with our DOR findings, we completed similar behavioral and electrophysiological experiments with MOR ligands.…”