Nalmefene is an opioid antagonist used to reduce alcohol consumption and treat and prevent opioid overdose. This drug is a 6-methylene analogue of naltrexone. It acts as an antagonist at the mu (μ)-opioid and delta (δ)-opioid receptors. As an antagonist, nalmefene blocks ligands from binding to the opioid receptor. It is administered as oral tablets, intravenous injections, or in a nasal spray formulation (approved by the FDA in May 2023). Animal studies suggest that kappa-opioid receptor signaling blocks the acute reward and positive reinforcement effects of drugs (like opioids) 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. Nalmefene inhibits the exchange of GTP for GDP which is required to activate the G-protein complex. This prevents the Gi subunit of the mu opioid receptor from inhibiting adenylate cyclase, which can therefore continue to catalyze ATP into cAMP. cAMP increases the excitability in spinal cord pain transmission neurons which allows the patient to feel pain rather than the analgesic effects of opioids. The inhibition of Mu-type opioid receptors also prevents the Gi subunit of the mu opioid receptor from activating the inwardly rectifying potassium channel increasing K+ conductance which would cause hyperpolarization. Nalmefene also prevents the gamma subunit of the mu opioid receptor from inhibiting the N-type calcium channels on the neuron. This allows calcium to enter the neuron and depolarize. The inhibition of mu-opioid receptors prevents hyperpolarization in the neuron, allowing it to fire at a normal rate. The neuron is able to depolarize and the high concentration of calcium releases GABA into the synapse which binds to GABA receptors. GABA receptors inhibits dopamine cell firing in the pain transmission neurons. This prevents the analgesic and depressive effects of opioids, preventing opioid overdose. GABA also inhibits dopamine cell firing in the reward pathway which is the main cause of addiction to opioids and other drugs.

Nalmefene Opioid Antagonist Pathway References