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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 × 10−4 M at NR1/NR2A and 6.3 ± 2.4 × 10−4 M at NR1/NR2B; racemic ketamine 13.6 ± 8.5 × 10−6 M at NR1/NR2A and 17.6 ± 7.2 × 10−6 M at NR1/NR2B; S(+)-ketamine 4.1 ± 2.5 × 10−6 at NR1/NR2A and 3.0 ± 0.3 at NR1/NR2B; R(−)-ketamine 24.4 ± 4.1 × 10−6 M at NR1/NR2A and 26.0 ± 2.4 × 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.