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.
*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
H-TL and W-HL are supported by a grant from the Rockefeller Foundation. MWH is supported in part by the Department of Anesthesiology (Direktor: Univ.-Prof. Dr. E. Martin), University of Heidelberg, Heidelberg, Germany, and by a grant of the German Research Society (DFG HO 2199/1-1), Bonn, Germany. Supported in part by the “Innovative Medizinische Forschung” fund, Münster, Germany, Grants Hö-1-6-II/96-8 and 1-6-II/97-27 to CWH, and by an American Heart Association grant, Mid-Atlantic affiliation (VHA 9920345 U), Baltimore, Maryland, and National Institutes of Health Grant GMS 52387, Bethesda, Maryland.
January 3, 2001.
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 firstname.lastname@example.org.
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.