Functional Inhibition by Methadone of N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes: Stereospecific and Subunit Effects

UNLABELLED Methadone is a strong opioid analgesic that is finding increasing use in chronic pain therapeutics. We explored its reported efficacy for inhibiting N-methyl-D-aspartate (NMDA) receptors in a functional electrophysiologic assay (Xenopus laevis oocyte expression). Racemic methadone inhibited all subtypes of rat NMDA receptors with derived 50% inhibitory concentrations in the low micromolar range. These concentrations overlap with clinically achievable concentrations reported in pharmacokinetic studies. In contrast, morphine inhibited these functional ion channels only at 8-16 times larger concentrations. The NR1/2A and NR1/2B subtype combinations were in general significantly more sensitive to inhibition by methadone and morphine compared with the NR1/2C and NR1/2D subtypes. In the presence of racemic methadone, the maximum NMDA-stimulated currents were markedly decreased, but the NMDA concentration producing 50% of maximal activation was altered only slightly, indicating that methadone blocks by a noncompetitive mechanism. Although stereoisomers of methadone showed minimal stereoselectivity in most subtypes, R(-) methadone was highly selective in its inhibition of the NR1/2A combination. These results provide further functional data describing the NMDA receptor inhibitory actions of methadone and support the hypothesis that methadone acts through both opioid and NMDA receptor mechanisms. IMPLICATIONS At clinically achievable concentrations, methadone inhibits functional N-methyl-D-aspartate receptors. These results indicate a unique mode of action by this opioid that may enhance its ability to treat chronic pain and to limit opioid tolerance.