Effects of Naltrexone on Alcohol Sensitivity and Genetic Moderators of Medication Response

Abstract

This study advances the knowledge of mechanisms of action of naltrexone and genetic moderators of response to this pharmacotherapy.

Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates

“…Similar to the rhOPRM1 C77G, a polymorphism encoding an amino acid substitution in the N-terminal arm of OPRM1 has independently arisen in humans (OPRM1 A118G) (14). Although its consequences at the molecular level remain to be fully elucidated (14,16,17,31,32), recent in vivo data support the notion that the OPRM1 118G is indeed a gain-of-function variant, because it is associated with increased pain threshold, increased sensitivity to euphorogenic effects of addictive drugs, increased cortisol response after challenge with the opioid antagonist naltrexone, and higher rates of therapeutic response to the opioid antagonist naltrexone in alcoholism (19,20,(33)(34)(35). Findings in rhesus macaques suggest that rhOPRM1 77G has a gain-of-function role as well (15,18), indicating the human and rhesus OPRM1 variants are functionally similar.…”

“…Although the exact mechanism remains unclear (16,17), in vivo data support a gain-of-function role for these variants, as shown, for example, by increased alcohol-induced stimulation, an effect mediated through release of endogenous opioids (18)(19)(20). The aim of the present study was to examine whether the rhOPRM1 77G allele would influence attachment behavior in rhesus macaque infants.…”

The Effects of Pharmacological Opioid Blockade on Neural Measures of Drug Cue-Reactivity in Humans

“…However, the absence of naltrexone-related reductions in self-reported craving may also be related to the craving assessment procedure used (ie, phasic measurement of craving with a single item during scanning) as other studies have observed a benefit of using expanded item and response sets for the detection of drug craving correlations with neural measures of cue-reactivity (Courtney and Ray, 2014b). Further, previous studies have demonstrated complete hydromorphone blockade following a single dose of naltrexone (25 or 100 mg; Preston and Bigelow, 1993;Schuh et al, 1999) and others have observed reductions in alcohol and drug craving following 3-day dosing of naltrexone (Ray and Hutchison, 2007), suggesting that the measurement limitation theory may be a more viable explanation for the lack of naltrexone-related tonic craving reductions observed in the present study. Lastly, an analytic limitation of the present study is the use of atlas-based approaches to defining common ROIs used for all subjects.…”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Such findings on safety and mechanisms are vital to deciding whether to invest resources for efficacy testing for a putative addiction medication. Our team has used human laboratory paradigms to test several medications for addiction, including naltrexone (Ray, Bujarski, Chin, & Miotto, 2012;Ray & Hutchison, 2007), topiramate (Miranda et al, 2008;Ray et al, 2009), quetiapine (Moallem & Ray, 2012;Ray, Chin, Heydari, & Miotto, 2011), and varenicline (Ray et al, 2014(Ray et al, , 2013. Given the new opportunities presented by recent discoveries on the role of neuroinflammation in addiction as well as new advancements in the technology of medication development, including the refinement of powerful human laboratory models, the stage is set for the discovery of novel treatments for substance use disorders.…”