Volatile anesthetics and NMDA receptors. Enflurane inhibition of glutamate-stimulated [³H]MK-801 binding and reversal by glycine

The influence of enflurane, a volatile general anesthetic, on [³H]MK-801 binding to a site in the ion channel of the N-methyl-d-aspartate (NMDA) receptor was determined in membranes from rat cerebral cortex. Enflurane disrupted glutamate stimulation of [³H]MK-801 (1 nM) binding with an IC₅₀ of 0.4 mM. This inhibition was associated with a decrease in receptor affinity with no change in the number of [³H]MK-801 binding sites. Basal [³H]MK-801 binding measured in the absence of glutamate was not affected by enflurane. In contrast, [³H]CGS-19775 binding to the glutamate recognition site on the NMDA receptor was only weakly inhibited by enflurane (e.g., less than 20% inhibition of 5 nM [³H]CGS binding by 1.2 mM enflurane). Glycine, a positive allosteric NMDA receptor modulator, markedly attenuated the inhibition of glutamate-stimulated [³H]MK-801 binding by enflurane, with an EC₅₀ of approximately 0.8 μM. Thus, enflurane selectively inhibits glutamate activation of the NMDA receptors, and an allosteric modulator attenuates this action. These effects could reflect anesthetic action at the glycine binding site or at another, undefined site which influences activation of the ion channel. These findings raise the possibility that inhibition of transmission at NMDA receptors contributes to the development of the anesthetic state.