Alcohol dependence and opioid receptor -Pharmacological profile of nalmefene

Abstract

Alcohol dependence is one of the psychiatric disorders affecting over 1 million people in Japan. Mesolimbic dopamine neuron projecting from ventral tegmental area to nucleus accumbens (Reward system) plays important roles in alcohol dependence including other dependence. Accumulating evidence indicates that the endogenous opioid system regulate this reward system. That is, alcohol stimulates the release of endogenous opioid peptides such as β-endorphin and dynorphin in the brain. β-endorphin activates μ-opioid receptor leading to euphoric mood and positive reinforcement, while dynorphin activates κ-opioid receptor leading to dysphoric mood and negative reinforcement. These euphoric/dysphoric mood and reinforcement effects via endogenous opioid systems are suggested to be implicated in repeated alcohol intake in patients with alcohol dependence. Nalmefene acts as an antagonist at μ- and δ-opioid receptor and a partial agonist at κ-opioid receptor. Preclinical studies have shown that nalmefene reduced the alcohol intake in alcohol preference rats. In clinical trials, as-needed use of nalmefene with psychosocial support reduced the number of heavy-drinking days and total alcohol consumption. These results suggest that nalmefene modulates the alcohol-induced euphoric/dysphoric mood via opioid system and thereby contribute to reduction in alcohol consumption in patients with alcohol dependence. Here, we summarize the implications of opioid system in alcohol dependence and pharmacological profiles of nalmefene in preclinical and clinical studies.