Direct Inhibition of the N-methyl-D-aspartate Receptor Channel by High Concentrations of Opioids

Background: Electrophysiologic and receptor binding studies showed that some opioids have noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist properties.

Methods: The effects and mechanisms of action of various opioid compounds were examined on four kinds of heteromeric NMDA receptor channels, namely the epsilon]1/zeta]1, epsilon]2/zeta]1, epsilon]3/zeta]1, and epsilon]4/zeta]1 channels, expressed in Xenopus oocytes. Furthermore, the action sites of opioids on NMDA receptor channels were investigated by site-directed mutagenesis.

Results: Meperidine inhibited four kinds of channels to a similar extent with inhibitor concentrations for half-control response (IC50s) of 210-270 mu]M. Morphine, fentanyl, codeine, and naloxone also inhibited NMDA receptor channels with affinities comparable to meperidine. Opioid inhibition exhibited voltage dependence and was quite effective at negative potentials. Opioids also shifted the inhibition curve of Mg2+ to the right. Furthermore, replacement of the conserved asparagine residue with glutamine in the channel-lining segment M2 of the zeta]1 subunit, which constitutes the block sites of Mg2+ and ketamine, reduced the sensitivity to opioids, whereas that of the epsilon]2 subunit barely affected the opioid sensitivity.