Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis

Dextromethorphan is a weak noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is metabolized in vivo to dextrorphan, a more potent noncompetitive NMDA antagonist that is the dextrorotatory enantiomer of the opioid agonist levorphanol. The present study characterized the effects of the acute administration of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal (HPA) axis in the rat and tested the involvement of opioid receptors in the responses produced by dextrorphan and levorphanol. Although both dextromethorphan and dextrorphan increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, the dextromethorphan-induced responses occurred more rapidly than the dextrorphan-induced responses. The analysis of plasma levels of dextrorphan produced after the administration of dextromethorphan indicates that the concentration of dextrorphan formed was too low to be pharmacologically relevant, suggesting that at least some of the effects on the HPA axis are due to the parent compound, and not the metabolite. Naloxone (2 mg/kg) had no effect on the dextrorphan-induced increases in plasma levels of ACTH and corticosterone, but it blocked the levorphanol-induced increases. These results support the hypothesis that dextromethorphan has pharmacological activity aside from its biotransformation to dextrorphan and demonstrate that the effects of dextrorphan are not mediated by opioid receptors.