Modulation of NMDA receptor function by ketamine and magnesium: Part I.

UNLABELLED: N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects of Mg2+, racemic ketamine and its isomers, and the combination of Mg2+ and S(+)-ketamine on NMDA signaling were determined. Mg2+ and ketamine alone inhibited NMDA receptors noncompetitively (half-maximal inhibitory effect concentration: Mg2+ 4.2 +/- 1.2 x 10(-)(4) M at NR1/NR2A and 6.3 +/- 2.4 x 10(-)(4) M at NR1/NR2B; racemic ketamine 13.6 +/- 8.5 x 10(-)(6) M at NR1/NR2A and 17.6 +/- 7.2 x 10(-)(6) M at NR1/NR2B; S(+)-ketamine 4.1 +/- 2.5 x 10(-)(6) at NR1/NR2A and 3.0 +/- 0.3 at NR1/NR2B; R(-)-ketamine 24.4 +/- 4.1 x 10(-)(6) M at NR1/NR2A and 26.0 +/- 2.4 x 10(-)(6) M at NR1/NR2B). The combined application of Mg2+ and ketamine decreased the half-maximal inhibitory effect concentration >90% at both receptors. Isobolographic analysis demonstrated super-additive interactions. Ketamine and Mg2+ inhibit responses of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone. IMPLICATIONS: Ketamine and Mg2+ inhibit functioning of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone.