The d- and l- isomers of methadone bind to the non-competitive site on the N-methyl- d-aspartate (NMDA) receptor in rat forebrain and spinal cord

Abstract

Racemic ( dl)-methadone has antagonist activity at the N-methyl- d-aspartate (NMDA) receptor. We evaluated dl-methadone, the opioid active ( l-) and the opioid inactive ( d-) isomers in competition binding assays. dl-Methadone and its d- and l- isomers exhibited low micromolar affinities for the [ 3H]MK-801-labeled non-competitive site of the NMDA receptor in both rat forebrain and spinal cord synaptic membranes, with K i values and displacement curves similar to those of dextromethorphan, an established NMDA receptor antagonist. They lacked affinity at the [ 3H]CGS-19755-labeled competitive site of the NMDA receptor. Therefore, both methadone and its the d- and l- isomers differ from morphine, hydromorphone, and naltrexone in that they have non-competitive antagonist activity at the NMDA receptor. A non-opioid NMDA receptor antagonist, such as d-methadone, may improve the efficacy of morphine by attenuating the development of tolerance.