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ANESTHETIC PHARMACOLOGY

Modulation of NMDA Receptor Function by Ketamine and Magnesium: Part I

Hong-Tao Liu, MD, Markus W. Hollmann, MD, Wei-Hua Liu, MD, Christian W. Hoenemann, MD, and Marcel E. Durieux, MD, PhD^*

*Department of Anesthesiology and Pain Management, University Hospital Maastricht, Maastricht, The Netherlands; Department of Anesthesiology, University of Virginia, Charlottesville, Virginia; Department of Anesthesiology and Intensive Care, University of Muenster, Muenster; and Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany

Address correspondence and reprint requests to Marcel E. Durieux, MD, PhD, Department of Anesthesiology and Pain Management, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Address e-mail to mdu{at}sane.azm.nl

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.

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