Nalmefene

The opioid system consists of three opioid receptors - mu (μ), delta (δ), and kappa (κ) - that are G-protein coupled receptors. Opioid receptors are activated by endogenous opioid peptides and are expressed throughout the brain to play a critical role in mood regulation, pain, reward, addictive behaviours, and substance use disorders. Opioid receptors are involved in various brain signalling pathways, including the mesolimbic pathway, sometimes referred to as the reward pathway. The mesolimbic pathway plays an important role in the positive reinforcement of natural rewards like food and drugs of abuse like exogenous opioid drugs. Many abused drugs activate mu-opioid receptors, leading to positive reinforcing effects. Alcohol consumption can also cause the release of endogenous opioids, which bind to mu and delta receptors, thereby increasing the release of dopamine in the nucleus accumbens to induce reward and positive reinforcement effects.

Nalmefene is an antagonist at the mu and delta-opioid receptors and a partial agonist at the kappa-opioid receptor. As an antagonist, nalmefene blocks ligands from binding to the opioid receptor. Animal studies suggest that kappa-opioid receptor signalling blocks acute reward and positive reinforcement effects of drugs with abusive potential by decreasing dopamine in the nucleus accumbens. In vivo studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions. Preclinical studies suggest that nalmefene restores alcohol-induced dysregulations of the MOR/endorphins and the KOR/dynorphin system.