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.