Levallorphan is an opioid antagonist similar to nalexone, which also has some agonist properties. Levallorphan is used to treat respiratory depression caused by opioid overdose. The partial agonist properties of levallorphan allow if to prevent respiratory depression while also maintaining some of the euphoria induced by the opioids. It mainly targets the mu opioid receptor, however some research indicates it has effects on the kappa opioid receptor, different from the mu opioid receptor which allow it to prevent respiratory depression while also maintaining euphoria. Respiratory depression is thought to occurs due to inhibition of the PreBötzinger complex in the medulla of the brainstem where breathing rhythm is controlled by CO2 concentrations.. Opioids inhibit this, causing respiratory depression through hyperpolarization, which lowers the sensitivity to CO2. However, Levallorphan has been found to increase respiratory depression caused by alcohol or other drugs. Levallorphan is speculated to antagonize Mu opioid receptors on post synaptic neurons in the PreBötzinger complex in the brainstem. This 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. With the mu opioid receptor unable to inhibit adenylate cyclase, it is able to synthesize cAMP which increases the excitability the PreBötzinger Complex in the brain which increases respiration. 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. Levallorphan 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. Levallorphan antagonizing the mu-opioid receptor prevents hyperpolarization which would cause respiratory depression and hypoxia. This, therefore, leads to regulation of breathing in those with opioid-induced respiratory depression.

Levallorphan Pathway (New) References