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ANESTHETIC PHARMACOLOGY

Modulation of NMDA Receptor Function by Ketamine and Magnesium. Part II: Interactions with Volatile Anesthetics

Markus W. Hollmann, MD, Hong-Tao Liu, MD, Christian W. Hoenemann, MD, Wei-Hua Liu, 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

	Abstract

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Mg²⁺ and ketamine interact superadditively at N- methyl-D-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg²⁺ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 µM on NR1/NR2A, 3.0 µM on NR2/NR2B) and/or Mg²⁺ (416 µM on NR1/NR2A, 629 µM on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 ± 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 ± 0.03 MAC for desflurane, 1.24 ± 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 ± 0.12 MAC for isoflurane, 1.22 ± 0.08 MAC for desflurane, and 1.28 ± 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg²⁺, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg²⁺, S(+)-ketamine, or—most profoundly—both. Therefore, the analgesic effects of ketamine and Mg²⁺ are likely to be enhanced in the presence of volatile anesthetics.

Implications: Clinically relevant concentrations of volatile anesthetics inhibit functioning of N-methyl-D-aspartate receptors expressed recombinantly in Xenopus oocytes. This inhibition is reversible, concentration-dependent and voltage-insensitive, and results from noncompetitive antagonism of glutamate/glycine signaling. In addition, these effects can be potentiated significantly by co-application of either Mg²⁺, S(+)-ketamine, or—most profoundly—both.

	Introduction

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In Part I of this investigation, we described the interactions between ketamine and Mg²⁺ at N- methyl-D-aspartate (NMDA) glutamate receptors. Mg²⁺ and ketamine interacted in a super-additive manner at both NR1/NR2A and NR1/NR2B receptors. The impetus for this study were clinical findings indicating that ketamine and Mg²⁺ have significant analgesic properties, and that the combination is more effective than either drug alone (1). Thus, by combining the compounds, additional benefit for the patient may be obtained without an increase in side effects. This issue may be relevant not only to the analgesic effects of NMDA receptor blockade, but also to its neuroprotective actions (2,3).

However, clinical preemptive analgesia with ketamine and Mg²⁺ takes place in the setting of surgery and anesthesia, and, therefore, the patient is usually exposed concomitantly to volatile anesthetics. Our experimental model as described in Part I is therefore not fully comparable with the clinical situation. Various lines of evidence suggest interactions between volatile anesthetics and NMDA receptor signaling. In addition, the potency of volatile anesthetics is increased by noncompetitive (4,5) and competitive (6) NMDA antagonists. This, in turn, suggests that at the NMDA receptor, volatile anesthetics might interact with ketamine and/or Mg²⁺, administered as analgesics. As a result, they may modulate the effect of these compounds. Inasmuch as it is not known whether volatile anesthetics selectively influence NMDA receptors of various subunit compositions, it is conceivable that interactions among these drugs may depend on the specific NMDA receptor present in relevant neurons.

Therefore, in this part of our investigation, we tested the hypothesis that volatile anesthetics, at clinically relevant concentrations, interact with ketamine and/or Mg²⁺ at recombinantly expressed NMDA receptors.

	Methods

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The study protocol was approved by the Animal Care and Use Committee at the University of Virginia.

Our methodology for receptor expression and study was as described in Part I of the investigation. Briefly, oocytes were obtained from Xenopus laevis frogs, defolliculated, and injected with cDNA encoding the appropriate NMDA receptor subunits. After allowing appropriate time for receptor expression, Ba²⁺ currents in response to glutamate were measured by using a two-electrode voltage clamp.

Isoflurane, sevoflurane, and desflurane were selected for the study because they are the compounds most frequently used in clinical practice in the United States. Anesthetic was bubbled for at least 10 min through a reservoir filled with 40 mL of Tyrode’s solution. Air, at a flow rate of 500 mL/min, was used as the carrier gas. After equilibration, the solution was perfused through the recording chamber, superfusing the oocyte at a flow rate of approximately 2 mL/min; measurements were obtained after 10 bath volumes had been exchanged (approximately 3 min). Anesthetic concentrations in the recording chamber were quantified by gas chromatography. To allow comparisons among the anesthetics, partial pressures were expressed as minimum alveolar anesthetic concentration (MAC) fractions, where aqueous concentrations equivalent to one MAC anesthetic in air were 0.23 mM for isoflurane, 0.14 mM for sevoflurane, and 0.26 mM for desflurane (7). For multiple experiments in the same oocyte, we superfused the cell with anesthetic-free Tyrode’s solution for at least 10 min, at which time current had returned completely to baseline.

Results were reported as mean ± SEM. Because variability between batches of oocytes is common, responses were at times normalized to control responses from the same batch. Differences among treatment groups were analyzed by using Student’s t-tests. If multiple comparisons were made, data were analyzed by using one-way analysis of variance followed by Dunnett’s post hoc test, if necessary. P < 0.05 was considered significant. Concentration-response curves were fit to the following logistic function, derived from the Hill equation: y = y_min + (y_max - y_min) (1 - xⁿ/[x₅₀ⁿ + xⁿ]) where y_max and y_min are the maximum and minimum response obtained, n is the Hill coefficient, and x₅₀ is the half-maximal effect concentration (EC₅₀ for agonist) or the half-maximal inhibitory effect concentration (IC₅₀ for antagonist).

Molecular biology reagents were obtained from Promega (Madison, WI). Isoflurane and desflurane were from Ohmeda (Liberty Corner, NJ), sevoflurane was from Abbott International (Abbott Park, IL), and other chemicals were obtained from Sigma Chemical Company (St. Louis, MO).

	Results

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Volatile Anesthetics Inhibit NMDA Receptor Signaling
To determine the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, we activated recombinantly expressed NR1/NR2A and NR1/NR2B receptors by co-application of glutamate and glycine in the presence of three different concentrations (1, 2, and 3 MAC) of the volatile anesthetics. Glutamate and glycine were administered at EC₅₀, which on NR1/NR2A and NR1/NR2B receptors were 3.2 µM and 4.9 µM, respectively, for glutamate, and 150 nM and 78 nM, respectively, for glycine, as determined in Part I of this research. All three anesthetics inhibited NMDA receptor signaling reversibly, dose-dependently, and equipotently.

At NR1/NR2A receptors ( Fig. 1A), IC₅₀, calculated from the Hill equation, were remarkably similar when expressed as MAC ( Table 1). The largest anesthetic concentration tested corresponded to 3 MAC. Even larger concentrations would be outside the clinical range, and might yield confusing results because of nonspecific actions. At 3 MAC, NMDA receptor signaling was suppressed 84% ± 3% by isoflurane, 87% ± 8% by desflurane, and 69% ± 10% by sevoflurane. The anesthetic effects at NR1/NR2B receptors (Fig. 1B, Table 1) were similar to those obtained at NR1/NR2A receptors. Inhibition at 3 MAC was 85% ± 3% for isoflurane, 76% ± 7% for desflurane, and 73% ± 3% for sevoflurane. These results suggest that the NR2 subunit does not greatly modulate anesthetic effects on the NMDA receptor, and that volatile anesthetics have their primary site of action on the NR1 subunit.

View larger version (19K): [in this window] [in a new window]   Figure 1. Volatile anesthetic inhibition of N-methyl-D-aspartate receptor signaling. A, Volatile anesthetic inhibition of NR1/NR2A receptor functioning. Half-maximal inhibitory concentration is 1.30 ± 0.02 minimum alveolar anesthetic concentration (MAC) for isoflurane, 1.18 ± 0.03 MAC for desflurane, and 1.24 ± 0.06 MAC for sevoflurane. Mean control peak current size is 2.5 ± 0.6 µA. B, Inhibition of NR1/NR2B receptors by volatile anesthetics. Calculated 50% inhibitory concentrations are 1.33 ± 0.12 MAC for isoflurane, 1.22 ± 0.08 MAC for desflurane and 1.28 ± 0.08 MAC for sevoflurane. Mean control peak current size is 2.38 ± 0.6 µA.

Volatile Anesthetics Inhibit Glutamate Signaling in a Noncompetitive Manner
We determined the concentration-response relationship for glutamate (in the presence of glycine at EC₅₀) on NR1/NR2A and NR1/NR2B receptors alone and in the presence of each of the three anesthetics (administered at IC₅₀). As shown in Figure 2A and B, and Table 1, each of the anesthetics decreased significantly (P < 0.001) the maximal glutamate effect (E_max). Thus, the inhibitory action of the anesthetics could not be overcome by large agonist concentrations. Even at millimolar concentrations of agonist, response sizes were reduced by >50%.

View larger version (35K): [in this window] [in a new window]   Figure 2. Volatile anesthetic interaction with glutamate and glycine signaling. A, Concentration-response relationship for glutamate on NR1/NR2A receptors in the absence (control) and presence of isoflurane, desflurane, or sevoflurane (at 50% inhibitory concentration [IC50]). Each of the anesthetics decrease significantly (P < 0.001) the maximal glutamate effect (Emax), from 3.4 ± 0.01 µA under control conditions to 2.1 ± 0.01 µA (isoflurane), 1.7 ± 0.01 µA (desflurane), and 2.1 ± 0.06 µA (sevoflurane). B, Effects of the anesthetics (at IC50) on glutamate signaling of NR1/NR2B receptors. Emax under control conditions is 2.5 ± 0.4 µA. This value decreases to 1.1 ± 0.03 µA with isoflurane, 1.2 ± 0.01 µA with desflurane, and 0.9 ± 0.05 µA with sevoflurane. C and D, Isoflurane, desflurane, and sevoflurane (at IC50) effects on glutamate signaling (50% effective concentration for glutamate) in the presence of various concentrations of glycine. The anesthetics decreases Emax (P < 0.05) without affecting 50% effective concentration. At NR1/NR2A receptors (C), Emax is 3.0 ± 0.1 µA under control conditions, but decreases to 1.9 ± 0.09 µA with isoflurane, 1.7 ± 0.08 µA with desflurane, and 1.6 ± 0.1 µA with sevoflurane. At NR1/NR2B receptors, Emax is 2.0 ± 0.1 µA under control conditions, and decreases to 1.5 ± 0.05 µA with isoflurane, 1.4 ± 0.1 µA with desflurane, and 1.6 ± 0.08 µA with sevoflurane.

Volatile Anesthetics Inhibit Glycine Signaling in a Noncompetitive Manner
Because glycine is an obligatory co-agonist at the NMDA receptor, its binding site could be a target for volatile anesthetic action. We therefore tested the effects of isoflurane, desflurane, and sevoflurane (at IC₅₀) on glycine signaling (in the presence of glutamate at EC₅₀). As indicated in Figure 2C and D, and Table 1, the anesthetics decreased E_max (P < 0.05) without affecting EC₅₀. Therefore, volatile anesthetics are unlikely to act on the agonist binding pocket for glycine, but inhibit glycine signaling by an allosteric antagonism.

Mg²⁺ Potentiates the Inhibitory Effect of Volatile Anesthetics on NMDA Receptor Signaling
Next we assessed whether Mg²⁺ enhances the inhibitory effect of volatile anesthetics on NMDA receptor signaling. On both NR1/NR2A and NR1/NR2B receptors, we determined the IC₅₀ for each volatile anesthetic alone, and in the presence of Mg²⁺ at IC₅₀ (416 µM at NR1/NR2A and 629 µM at NR1/NR2B) ( Fig. 3, Table 1). IC₅₀ was shifted significantly to the left in the presence of Mg²⁺. On NR1/NR2A receptors, the reduction in IC₅₀ was 28% (P = 0.02, t-test) for isoflurane, 16% (P = 0.038, t-test) for sevoflurane, and 24% (P = 0.035, t-test) for desflurane. On NR1/NR2B receptors, the shift was 30% (P < 0.001, t-test) for isoflurane, 12% (P = 0.028, t-test) for sevoflurane, and 14% (P = 0.024, t-test) for desflurane. There were no significant differences among the three anesthetics for NR1/NR2A receptors (P = 0.624), whereas for NR1/NR2B receptors, inhibition by isoflurane was significantly more (P < 0.05, analysis of variance, Student-Newman-Keuls) than by the other two anesthetics. Hill coefficients were similar in the presence and absence of Mg²⁺.

View larger version (30K): [in this window] [in a new window]   Figure 3. Mg2+ potentiates volatile anesthetic inhibition of N-methyl-D-aspartate receptor signaling. Concentration-inhibition curves for each volatile anesthetic alone and in the presence of Mg2+ at 50% inhibitory concentration (IC50). N-methyl-D-aspartate receptors were stimulated by glutamate and glycine at 50% effective concentration. Half-maximal inhibition concentration is significantly shifted to the left in the presence of Mg2+. At NR1/NR2A receptors, Mg2+ reduces IC50 for isoflurane by 28% (A), sevoflurane by 16% (C), and desflurane by 24% (E). For NR1/NR2B receptors, reduction in IC50 is 30% for isoflurane (B), 12% for sevoflurane (D), and 14% for desflurane (F). Mean control peak currents are comparable for each experiment (2.5 ± 0.7 µA). MAC = minimum alveolar anesthetic concentration.

S(+)-Ketamine Potentiates Inhibition of NMDA Receptor Signaling by Volatile Anesthetics
To determine whether S(+)-ketamine also enhances volatile anesthetic inhibition of NMDA receptor functioning, we applied several concentrations of each anesthetic in the presence of S(+)-ketamine at IC₅₀ (4.0 µM [NR1/NR2A] and 2.9 µM [NR1/NR2B]), and determined the anesthetic IC₅₀ ( Fig. 4, Table 1). As did Mg²⁺, S(+)-ketamine attenuated the anesthetic concentration required to achieve half-maximal inhibition. On NR1/NR2A receptors, calculated IC₅₀ was reduced by 30% (P < 0.001, t-test) for isoflurane, 33% (P = 0.004, t-test) for sevoflurane, and 24% (P = 0.004, t-test) for desflurane. On NR1/NR2B receptors, IC₅₀ was reduced by 38% (P = 0.001, t-test) for isoflurane, 33% (P < 0.001, t-test) for sevoflurane, and 24% (P = 0.006, t-test) for desflurane. In contrast to the findings with Mg²⁺, Hill coefficients were increased significantly in the presence of S(+)-ketamine. Although in the presence of multiple binding sites Hill coefficients are difficult to interpret (8), this difference between Mg²⁺ and ketamine suggests different modes of interaction among these drugs and volatile anesthetics.

View larger version (29K): [in this window] [in a new window]   Figure 4. S(+)-ketamine potentiates volatile anesthetic inhibition of N-methyl-D-aspartate receptor signaling. Concentration-inhibition relationship for volatile anesthetics alone and while administering S(+)-ketamine at 50% inhibitory concentration (IC50). N-methyl-D-aspartate receptors were stimulated by glutamate and glycine at 50% effective concentration. S(+)-ketamine decreases the minimum alveolar anesthetic concentration (MAC) required to achieve half-maximal inhibition on NR1/NR2A receptors for isoflurane (A) by 30%, for sevoflurane (C) by 33%, and for desflurane (E) by 24%. MAC-reducing effects on NR1/NR2B receptors are 38% for isoflurane (B), 33% for sevoflurane (D), and 24% for desflurane (F). Mean control peak currents are comparable for each experiment (2.7 ± 0.6 µA).

View larger version (28K): [in this window] [in a new window]   Figure 5. Combined administration of Mg2+ and S(+)-ketamine further potentiates inhibition of N-methyl-D-aspartate receptor functioning by volatile anesthetics. Inhibitory action of isoflurane, sevoflurane, and desflurane on glutamate/glycine (at 50% effective concentration)-induced N-methyl-D-aspartate receptor currents in the presence and absence of Mg2+ and S(+)-ketamine (both at 50% inhibitory concentration [IC50]). The minimum alveolar anesthetic concentration (MAC) required for half-maximal inhibition of NR1/NR2A signaling is reduced for isoflurane (A) by 56%, for sevoflurane (C) by 50%, and for desflurane (E) by 42%. For NR1/NR2B receptors, the left shift of IC50 is 55% for isoflurane (B), 51% for sevoflurane (D), and 43% for desflurane (F). Mean control peak currents are comparable for each experiment (2.4 ± 0.4 µA).

	Discussion

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Our results provide additional evidence for functional effects of clinical concentrations of volatile anesthetics on NMDA receptors. Such interactions are reported variably in the literature. Kirson et al. (9) found NMDA receptors to be relatively insensitive to halothane in concentrations <0.64 mM. IC₅₀ for halothane on NMDA receptors in these studies was approximately 5.9 mM. In agreement with our data, these investigators showed a voltage-independent mechanism for volatile anesthetic inhibition of NMDA receptors. Black (10) suggests that enflurane increases NMDA receptor activity (consistent with the epileptiform discharges observed during anesthesia with this agent). A study by Pearce et al. (11) showed that volatile anesthetics do not block NMDA receptors in rat hippocampus, because long-term potentiation (which is inhibited by NMDA receptor antagonists) still occurred in the presence of 1.5–2.1 MAC of volatile anesthetic. Many of these studies have limitations (receptor subunit composition not defined, or no functional measurements obtained), and the discrepancies among these studies and those mentioned below are likely attributable to the model systems used.

In contrast to these reports, our findings are in agreement with many studies supporting anesthetic interference with NMDA glutamate signaling. Isoflurane blocks NMDA-stimulated currents in cultured hippocampal neurons (12). Volatile anesthetics (IC₅₀ for isoflurane 0.6–0.9 mM) depress glutamate-dependent intraneuronal translocation of Ca²⁺ (13), and halothane (0.8 mM) and enflurane (1 mM) (14) block NMDA receptor function (15). Glutamate (100 µM)-stimulated [³H]MK-801 binding to the NMDA receptor was suppressed by halothane and enflurane (16,17). Eighty percent xenon reduced NMDA-activated currents by approximately 60% in a noncompetitive manner, suggesting that the NMDA receptor is instrumental in the anesthetic and analgesic effects of this compound (18). Nitrous oxide was suggested to be a mixed competitive/noncompetitive NMDA antagonist (19).

It is of interest that we found volatile anesthetics to be mainly equipotent in their effects on NMDA glutamate signaling despite differences in the corresponding millimolar concentrations. In addition, the measured IC₅₀ values were very close to 1 MAC for each of the three compounds. This relationship between anesthetic potency and ability to inhibit NMDA receptors suggests that inhibition of NMDA glutamate signaling in the brain and spinal cord may contribute considerably to the anesthetic state. This hypothesis has been formulated previously (20), and our findings support it completely. If so, our results suggest that the administration of ketamine and Mg²⁺ should have a noticeable effect on volatile anesthetic requirements: in the presence of concentrations of ketamine and Mg²⁺ as used in this study, the IC₅₀ of volatile anesthetics on NMDA receptors is shifted to approximately 0.5 MAC (Fig. 5). It would be of interest to test this hypothesis in a clinical study.

In addition, similar effects on NMDA signaling might help to explain why anesthetics with very different effects on cerebral metabolic rates have similar neuroprotective properties (21).

Both S(+)-ketamine and Mg²⁺ enhanced the inhibitory potency of volatile anesthetics on NMDA receptor signaling. These findings can explain results from animal studies showing a dose-dependent volatile anesthetic sparing effect of NMDA receptor antagonists. In rabbits, MK-801 (dizoclipine, plasma level 103 ± 28 ng/mL), a noncompetitive NMDA receptor antagonist, reduced MAC requirements for halothane and isoflurane by 46% and 67%, respectively (4). Whereas 0.3 µM MK-801 decreased isoflurane MAC by 67%, it required an approximately 10-fold larger concentration of S(+)-ketamine (4 µM) to increase isoflurane sensitivity by 30% in our model. This difference is probably attributable to an at least 10-fold more potency of MK-801 as compared with ketamine. Similar results have been reported for other noncompetitive NMDA receptor blockers, like phencyclidine (5), as well as for competitive NMDA receptor antagonists like _D-CPP-ene and CGS 19755 (Selfotel) (22). The ability of Mg²⁺ to decrease MAC has similarly been documented (23).

The combined application of ketamine and Mg²⁺ has not been studied. In our study, the combination profoundly enhanced inhibition of NMDA receptor functioning by volatile anesthetics, to the point in which clinically relevant concentrations of the compounds virtually eliminated NMDA receptor signaling. This has implications for neuroprotective and analgesic effects of these compounds. Selective noncompetitive and competitive NMDA receptor antagonists protect against focal cerebral ischemia (24). In agreement, ketamine is neuroprotective, with the S(+)-isomer being significantly more effective than the R(-) form (3). Mg²⁺ appears to have only a modest protective effect. Its benefit may be limited by the depolarization that takes place in damaged neurons, which in turn limits the (voltage-dependent) ability of Mg²⁺ to block NMDA receptors. The neuroprotective actions of volatile anesthetics are also thought to be mediated in part by inhibition of glutamate signaling (25). Volatile anesthetics with very different effects on cerebral metabolic rate show relatively similar neuroprotective potencies; this is in agreement with our findings of similar potency at the NMDA receptor. Our results suggest that combinations of these compounds might be significantly more effective than either compound used alone.

	Acknowledgments

 
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, MD, and National Institutes of Health Grant GMS 52387, Bethesda, MD.

We thank Prof. Dr. med. Eike Martin (Ruprecht-Karls-Universität Heidelberg, Germany) and Prof. Dr. med. Hugo Van Aken (Westfälische-Wilhelms-Universität Muenster, Germany) for their support. Sincere thanks to Dagmar Westerling, MD, PhD, for a preliminary analysis of the results.

	References

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				R. Brosnan, D. Gong, J. Cotten, B. Keshavaprasad, C. S. Yost, E. I. Eger II, and J. M. Sonner Chirality in Anesthesia II: Stereoselective Modulation of Ion Channel Function by Secondary Alcohol Enantiomers. Anesth. Analg., July 1, 2006; 103(1): 86 - 91. [Abstract] [Full Text] [PDF]

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				T. Yamakura, A. R. Askalany, A. B. Petrenko, T. Kohno, H. Baba, and K. Sakimura The NR3B Subunit Does Not Alter the Anesthetic Sensitivities of Recombinant N-Methyl-d-Aspartate Receptors Anesth. Analg., June 1, 2005; 100(6): 1687 - 1692. [Abstract] [Full Text] [PDF]

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