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Anesth Analg 2006;102:1397-1406
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000219019.91281.51

ANESTHETIC PHARMACOLOGY

Section Editor:
James G. Bovill

Contrasting Roles of the N-Methyl-d-Aspartate Receptor in the Production of Immobilization by Conventional and Aromatic Anesthetics

Edmond I. Eger, II, MD*, Mark Liao, BS*, Michael J. Laster, DVM*, Albert Won, MS*, John Popovich, BS*, Douglas E. Raines, MD{dagger}, Ken Solt, MD{dagger}, Robert C. Dutton, MD*, Franklin V. Cobos, II, MD{ddagger}, and James M. Sonner, MD*

Received from the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, the {dagger}Department of Anesthesia and Critical Care, Massachusetts General Hospital and Department of Anaesthesia, Harvard Medical School, Boston Massachusetts, and {ddagger}Department of Anesthesiology, University of Nebraska, Omaha, Nebraska

Address correspondence to Dr. Edmond I Eger II, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143–0464. Address e-mail to egere{at}anesthesia.ucsf.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We hypothesized that N-methyl-d-aspartate (NMDA) receptors mediate some or all of the capacity of inhaled anesthetics to prevent movement in the face of noxious stimulation, and that this capacity to prevent movement correlates directly with the in vitro capacity of such anesthetics to block the NMDA receptor. To test this hypothesis, we measured the effect of IV infusion of the NMDA blockers dizocilpine (MK-801) and (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) to decrease the MAC (the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects given a noxious stimulation) of 8 conventional anesthetics (cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon) and 8 aromatic compounds (benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene) and, for comparison, etomidate. We postulated that MK-801 or CPP infusions would decrease MAC in inverse proportion to the in vitro capacity of these anesthetics to block the NMDA receptor. This notion proved correct for the aromatic inhaled anesthetics, but not for the conventional anesthetics. At the greatest infusion of MK-801 (32 µg · kg–1· min–1) the MACs of conventional anesthetics decreased by 59.4 ± 3.4% (mean ± sd) and at 8 µg · kg–1· min–1 by 45.5 ± 4.2%, a decrease not significantly different from a 51.4 ± 19.0% decrease produced in the EC50 for etomidate, an anesthetic that acts solely by enhancing {gamma}-amino butyric acid (GABA) receptors. We conclude that some aromatic anesthetics may produce immobility in the face of noxious stimulation by blocking the action of glutamate on NMDA receptors but that conventional inhaled anesthetics do not.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Several observations suggest that glutamate NMDA (N-methyl-D-aspartate) receptors might mediate anesthesia produced by inhaled anesthetics, particularly immobility in the face of noxious stimulation. Blockade of NMDA receptors clearly underlies much or all of the anesthesia produced by ketamine (1). NMDA receptors located in lamina I and II of the spinal cord may mediate pain transmission (2). NMDA receptors may excite motor neurons (3) and may affect rhythmical activity of patterned movement (4). In spinal cord slices, ethanol (5) and volatile anesthetics (6) depress currents evoked by glutamate application by actions independent of gamma-amino butyric acid (GABA)A and glycine receptors, suggesting that anesthetic reduction of motor output can result from depression of excitation. Clinical and experimental inhaled anesthetics inhibit NMDA receptors at concentrations surrounding MAC (the minimum alveolar concentration of an inhaled anesthetic required to prevent movement in 50% of subjects given a noxious stimulation – i.e., an anesthetic EC50; Table 1). Isoflurane, sevoflurane and desflurane inhibit recombinant NR1/NR2A and NR1/NR2B NMDA receptors in a reversible, dose-dependent and voltage-insensitive manner (7). Similarly, enflurane, urethane, nitrous oxide, xenon, cyclopropane and butane inhibit NMDA-stimulated currents in oocytes expressing NMDA receptors (8–11). Nitrous oxide, cyclopropane and xenon are more potent than some inhaled anesthetics in their in vitro effects on NMDA receptors (12,13).


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  		Table 1. Change in MIC Produced by Intravenous Infusion of Dizocilpine (MK-801)

 

MK-801 (dizocilpine) blocks the action of glutamate on NMDA receptors. Application of glutamate normally increases binding of MK-801, which thereby serves as an indication of NMDA receptor activity. Thus, the decrease in binding produced by volatile anesthetics reflects their capacity to depress NMDA receptors (14). Diethyl ether, chloroform, methoxyflurane, halothane, enflurane, and isoflurane decrease glutamate-stimulated binding of MK-801 to the NMDA receptor.

MK-801 administration via various routes to rats decreases isoflurane MAC. The decrease primarily correlates with MK-801 concentrations in spinal cord (15), rather than whole brain or cerebral cortex concentrations, a finding consistent with spinal cord mediation of the immobility produced by inhaled anesthetic (16). Ishizaki et al. (17) found a maximal decrease of 30% in isoflurane MAC in rats given intrathecal bolus doses of the NMDA antagonists AP5, MK-801, (R)-4-(3-phophonopropyl)piperazine-2-carbolic acid (CPP), and 7CKA. Masaki et al. (18) applied the NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) intracerebroventricularly and noted a sevoflurane MAC-sparing effect, suggesting that NMDA receptors also might affect MAC by a supraspinal effect. McFarlane et al. (19) reported an 80% decrease in MAC of halothane from IV application of the competitive NMDA receptor antagonist CGS 19755.

The present study uses a simple premise to explore the relevance of NMDA receptors to the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation. In vitro studies find that conventional and experimental inhaled anesthetics block NMDA receptors with various potencies (13). Some anesthetics produce only a 13%-to-16% inhibition of normalized current at MAC, while others produce a 60%–70% blockade at MAC. We propose that if NMDA receptors mediate the effect of anesthesia with inhaled anesthetics, then IV administration of a drug such as MK-801 that blocks NMDA receptors will have less effect on the MAC values of anesthetics that are more potent blockers. That is, if an inhaled anesthetic potently blocks NMDA receptors, the MK-801 would have nothing further to block and thus would have little or no effect. The present study tests that hypothesis, making use of new data that precisely define the in vitro potency of the anesthetics applied in the present study (13).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Desflurane and isoflurane were obtained from Baxter Healthcare Corp. (New Providence, NJ); cyclopropane from Specialty Gases of America (Toledo, OH), enflurane from Anaquest (Liberty Corner, NJ), halothane from Halocarbon (River Edge, NJ), nitrous oxide from Puritan-Bennett (Lenexa, KS), sevoflurane and etomidate from Abbott Laboratories (North Chicago, IL), and xenon from Airgas (Sacramento, CA). Two aromatic compounds (benzene and fluorobenzene) were obtained from Sigma-Aldrich (St. Louis, MO), two others (o-difluorobenzene and hexafluorobenzene) from SunQuest Labs (Alachua, FL), and the remainder (p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, and pentafluorobenzene) from Apollo Scientific (Stockport, Cheshire, UK). MK-801 and CPP were obtained from Sigma-Aldrich.

With approval of the Committee on Animal Research of the University of CA, San Francisco, we studied male (Crl:CD(SD)BR) rats weighing 250– 450 g obtained from Charles River Laboratories (Hollister, CA). Rats were housed in rooms with daily cycles of 12 h of light and 12 of dark and had water and standard rat chow ad lib. At least 24 h before study, IV catheters made of PE 10 were placed in the right internal jugular vein under isoflurane anesthesia, and the open end of the catheter was tunneled to the ear where it exited and could be accessed.

MK-801 Dose-Response Studies
The study anesthetics were isoflurane and xenon. For isoflurane, MAC was determined concurrently in four rats placed in individual clear plastic cylinders. A rectal temperature probe was inserted, and the temperature probe and the tail of the rat were separately drawn through holes in the rubber stopper used to seal one end of the cylinder. Ports through the rubber stoppers in each end of the cylinder allowed gas delivery at the head end of the cylinder and exit of gas at the tail. A total flow rate of 4 L/min of oxygen and isoflurane was delivered (average 1 L/min per cylinder), and the exiting gases were scavenged. An isoflurane concentration estimated to be less than MAC was administered for 40 min, after which the tail was clamped and moved for up to 1 min (less if the rat moved). After certifying that movement had occurred, the concentration was increased by 20%–25%, and after a 40 min period of equilibration the tail clamp was again applied and movement or lack of movement determined. This process continued until all rats failed to move in response to application of the tail clamp. MAC was calculated as the average of the greatest concentration that permitted movement and the smallest concentration that suppressed movement.

For studies of xenon, MAC was determined in two rats simultaneously. Each rat was placed in a clear plastic tube closed at the distal end with a rubber stopper pierced with several holes. A rectal temperature probe and the rat’s tail were separately drawn through two of these holes. Four pairs of platinum needle electrodes were placed subcutaneously in the tail, and the tail was secured to an extension of the clear plastic tube. The tube containing each rat then was placed in a clear plastic hyperbaric chamber (i.e., a tube within a tube). The chamber was equipped with a carbon dioxide absorber and fan for circulating gases, and ports for introducing oxygen and xenon, for sampling gases, and for a connection to the IV catheter. The temperature probe and electrodes were connected to electrical pass-throughs, and the catheter to an external catheter connected, in turn, to an infusion pump. The combined deadspace volume of the IV and connecting catheters for both the isoflurane and xenon studies equaled approximately 17 µL. Electrical current delivered via the electrodes was used to stimulate the tail in lieu of a tail clamp; this approach produces the same MAC as when a tail clamp is used (20). After flushing the chamber with oxygen to produce an exiting partial pressure >95% of an atm, the chamber was sealed and the pressure brought to one atm.

Xenon then was introduced to produce approximately 1 atm partial pressure (2 atm total pressure) and equilibration continued for 30 min. Electrical stimulation to the tail was applied for one min or until the animal moved. The xenon concentration then was measured by gas chromatography and corrected to a partial pressure by accounting for the total pressure in the chamber. If the animal moved, we increased the xenon partial pressure by 0.15–0.3 atm. After equilibration for 30 min, the electrical stimulation was applied again and xenon partial pressure measured by chromatography. This procedure was repeated until the partial pressures bracketing movement-none movement were determined for each rat, and MAC was calculated as the average of these concentrations.

Two sets of experiments were performed for xenon and one set for isoflurane. All began with the determination of MAC during IV infusion of saline. Having completed this determination, the first group given xenon then received an infusion of 0.5 µg · kg–1 · min–1 of MK-801, and MAC was determined during this infusion and then during an infusion of 2.0 µg ·kg–1 · min–1 and then 8.0 µg · kg–1 · min–1. Similarly, after determination of MAC during infusion of saline, the second group received infusions of 8.0, 32, and 64 µg · kg–1 · min–1 of MK-801, and MAC was determined during these infusions. Rats anesthetized with isoflurane received successive infusions of 0, 2, 8, 32, and 64 µg · kg–1 · min–1 of MK-801, and MAC was determined for each infusion. All infusions of MK-801 began with a flush of the MK-801 solution sufficient to clear the catheter and add the equivalent of what would be infused in the course of approximately a half hour of infusion at the target rate. For all solutions (including normal saline), the infusion rate thereafter was 2 mL per hour. In this and all the succeeding investigations we studied 4-to-10 rats per anesthetic and drug dose. Deaths or technical difficulties occasionally decreased the number to 3.

MK-801 Single-Dose Studies
We had hoped to apply the above approach to all test anesthetics. However, results from preliminary studies with o-difluorobenzene revealed that this anesthetic had toxic effects – a few rats died. In addition, some anesthetics had relatively great solubilities, and thus the inspired concentrations (the measured concentration) might represent different alveolar concentrations after different durations of anesthetic delivery. Accordingly, for all remaining studies, we determined a single MAC of all test anesthetics during infusion of either saline (control; no MK-801), 8 µg · kg–1 · min–1 MK-801, or 32 µg · kg–1 · min–1 MK-801 (i.e., a given rat received only one dose of MK-801 and had only one MAC determination). The test anesthetics were: cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon, plus the aromatic compounds benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene. In all these studies, MAC was determined using electrical stimulation of the tail. In these and the CPP studies (next paragraph), an initial loading infusion 5 times the maintenance infusion was given for 5 min at the start of study. In all studies, the initial infusion rate was held constant for 45 min to allow equilibration before the first stimulation. Subsequent increases in the concentration were followed by 20–40 min of equilibration before applying the next stimulation. Studies of the MAC of nitrous oxide were conducted as described above for xenon, and the studies of MAC of the remaining anesthetics were conducted as described above for isoflurane.

CPP Single-Dose Studies
As noted above, we studied the effect of two infusion rates of the non-competitive NMDA blocker MK-801 for all test anesthetics. To determine whether the results obtained were unique to that form of blockade, we used the approach described for MK-801 in the previous paragraph to determine the effect of the competitive blocker CPP at a single infusion rate that approximated (as determined in preliminary studies) the effect of 8 µg · kg–1 · min–1 MK-801. These studies examined the effect of 4 mg/rat/hour (530 ± 10 µg · kg–1 · min–1; mean± sd) CPP on the MACs of cyclopropane, sevoflurane, hexafluorobenzene, 1,2,4-trifluorobenzene, and o-difluorobenzene. The experiments were limited to this infusion rate and these representative anesthetics because of the cost of CPP ($900 per experiment).

Effect of 8.0 µg · kg–1 · min–1 MK-801 on the MAC of Etomidate
We asked if the effect of MK-801 on MAC seen in the main experiment with inhaled anesthetics (two paragraphs above) would differ for an anesthetic whose effect was clearly not mediated by NMDA receptors. Etomidate is such an anesthetic, acting primarily by enhancing the response of GABAA-R to GABA (21,22). As described above, rats were prepared 1–2 days before study by placing a catheter in the internal jugular vein. We placed a second catheter in the carotid artery and tunneled both catheters out through the ear. The rats were divided into two groups. In the control group, 8 mg/hr etomidate was infused for 5 min and then for 30 min at 2 mg/hr. Electrical stimulation of the tail at the end of this infusion evoked movement in all rats. The infusion was increased to 3 mg/hr for 20 min and again stimulation produced movement. Further 20 min step increases of approximately 20% above the previous infusion rate were made until immobility was produced in one or more rats. When immobility was produced in a given rat, an arterial blood sample was taken and later analyzed for etomidate as described previously (23). In the experimental group, etomidate plus MK-801, 8 µg · kg–1 · min–1 MK-801, were infused IV concurrently with a step-wise increase in infusion of etomidate (MK-801 infusion constant). In these studies, the initial rate of infusion of etomidate was half that used in the control studies. As with the control group, when a rat exhibited immobility to noxious stimulation, an arterial blood sample was obtained for etomidate analysis.

Analyses of Inhaled Anesthetics
We used a Gow-Mac gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) equipped with a flame ionization detector to measure concentrations of carbon-containing compounds. The 4.6 meter-long, 0.22 cm internal diameter (ID) column was packed with SF-96. The column temperature was 100°C-200°C. The detector was maintained at temperatures approximately 50°C warmer than the column. The carrier gas flow was nitrogen at a flow of 15–20 mL/min. The detector received 35–38 mL/min hydrogen and 240–320 mL/min air. Primary standards were prepared for each compound, and the linearity of the response of the chromatograph was determined. We also commonly used secondary (cylinder) standards referenced to primary standards for some anesthetics (e.g., isoflurane).

For analysis of nitrous oxide and xenon, we used a thermal conductivity detector gas chromatograph (Gow-Mac 580, Bethlehem, PA) equipped with a 3-m-long, 3-mm ID column containing Hayesep D 100/120 maintained at 81°C with a 10 mL/min carrier flow of helium. The detector was maintained at 110°C. The chromatograph was calibrated before and at intervals during each test using primary standards.

Statistical Analyses
For the studies of xenon and isoflurane in which multiple determinations of MAC were made, we calculated the percent decrease in MAC from the MAC obtained during infusion of saline, each rat serving as his own control. For the studies in which only one MAC was obtained for a given rat (all test anesthetics), we used the average of the MAC determined in rats given an infusion of saline (control) and calculated the decrease from this control in each rat at 8 and at 32 µg · kg–1 · min–1 MK-801 infusions and at 530 µg · kg–1 · min–1 CPP. The mean and SD for each MK-801 dose, and for the CPP dose, was calculated and compared among anesthetics using ANOVA. Results for aromatic compounds and separately for the remaining anesthetics, were subjected to least squares linear regression analyses applied to both the raw data and the mean data. A Student’s t-test was used to compare the MAC values measured in the control group with those measured in the experimental group.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Infusion of MK-801 decreased MAC values for both isoflurane and xenon, doing so by approximately 50% (Fig. 1). Most of the effect of MK-801 was obtained with an infusion of 8 µg · kg–1 · min–1, and only modest or slight additional decreases were observed at 32 and 64 µg · kg–1 · min–1.


Figure 119
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  		Figure 1. Successively greater infusions of MK-801 decrease the MAC of isoflurane and xenon. It appears that an infusion of 32 µg · kg–1 · min–1 produces a maximum effect and 64 µg · kg–1 · min–1 does not cause a further decrease in MAC.

 

Infusion of 8 µg · kg–1 · min–1 MK-801 decreased MAC by 45.5 ± 4.2% for anesthetics not containing a benzene ring (Fig. 2; Table 2) [(36,37)]. However, for aromatic anesthetics, infusion of 8 µg · kg–1 · min–1 MK-801 produced a range of decreases in MAC that varied inversely with the in vitro capacity of these anesthetics to block NMDA receptors. For aromatic anesthetics, the percent decrease in the mean MAC values = 86 – 43*log (percent in vitro inhibition), with a correlation coefficient squared of 0.51 and P < 0.05 (i.e., the slope differed significantly from zero). For conventional anesthetics, the percent decrease in MAC = 55 – 6.3*log (percent in vitro inhibition), with a correlation coefficient squared of 0.08 (P = 0.51; not significant). The preceding analysis used the changes in the mean MAC values, thereby equally weighting the results for each anesthetic. When the raw data were analyzed, the results were identical except that the results for the aromatic compounds increased in significance (slope = 43 ± 11; P < 0.001). Significance for the anesthetics not containing a benzene ring did not increase (P = 0.75).


Figure 219
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  		Figure 2. An infusion of MK-801 at 8 µg · kg–1 · min–1 decreases the MAC of 8 conventional anesthetics by 45.5 ± 4.2% (mean± sd) with a poor correlation with the capacity of the anesthetic to inhibit the NMDA receptor in vitro. For conventional anesthetics, Y = 55 – 6.3*logX with a correlation coefficient squared of 0.08. In contrast, for the aromatic compounds a correlation does exist: Y = 86 – 43*logX with a correlation coefficient squared of 0.51.

 

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  		Table 2. Potency Values for the 16 Test Anesthetics With and Without Administration of MK-801

 

Infusion of 32 µg · kg–1 · min–1 MK-801 decreased MAC by 59.4 ± 3.4% for anesthetics not containing a benzene ring (Fig. 3; Table 2). This decrease significantly exceeded the decrease found with 8 µg ± · ± kg–1 ± · ± min–1 MK-801 (P < 0.001). However, infusion of 32 µg·kg–1·min–1 MK-801 produced a range of decreases in the MAC of aromatic anesthetics that varied inversely with the in vitro capacity of these anesthetics to block NMDA receptors. For the mean values for the aromatic anesthetics, the percent decrease in MAC = 118 – 62*log (percent in vitro inhibition), with a correlation coefficient squared of 0.94 (P < 0.001). For the mean values for conventional anesthetics, the percent decrease in MAC = 77 – 12*log (percent in vitro inhibition), with a correlation coefficient squared of 0.40 did not reach significance (P = 0.095). When the raw data were analyzed, the results were identical except that the results for the aromatic compounds increased in significance (slope = 60 ± 7; P < 0.001). The confidence interval for the anesthetics not containing a benzene ring increased, but still did not reach significance (P = 0.068)


Figure 319
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  		Figure 3. An infusion of MK-801 at 32 µg · kg–1 · min–1 decreases the MAC of 8 conventional anesthetics by 59.4 ± 3.4% with a small (not significant) correlation with the capacity of the anesthetic to inhibit the NMDA receptor in vitro. For conventional anesthetics, Y = 77 – 11.5*logX with a correlation coefficient squared of 0.40. In contrast, for the aromatic compounds a correlation does exist: Y = 118 – 61.6*logX with a correlation coefficient squared of 0.94.

 

Infusion of 530 µg·kg–1·min–1 CPP decreased MAC by 40.5 ± 2.9% for sevoflurane, cyclopropane, and hexafluorobenzene (Table 3), a value not significantly (t = 2.28 with 4 df) less than that obtained with 8 µg·kg–1·min–1 MK-801 for these three anesthetics (47.1 ± 4.1%). As with infusion of 8 µg·kg–1·min–1 MK-801, CPP produced no decrease in the MAC value for o-difluorobenzene and a 23% decrease in the MAC values for, 1,2,4-trifluorobenzene. That is, qualitatively and quantitatively, the results with CPP were similar to those obtained with administration of 8 µg·kg–1·min–1 MK-801 (Fig. 4). For the raw data for the aromatic compounds, the MAC change with CPP infusion correlated with the in vitro effect at MAC on current through the NMDA receptor: r2 = 0.92; the slope = – 81 ± 8; P < 0.001 (slope significantly different from zero).


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  		Table 3. Chan ge in MIC Produced by Intravenous Infusion of (R)-4-(3-Phosphonopropyl) Piperazine-2-Carboxylic Acid (CPP)

 

Figure 419
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  		Figure 4. The competitive blocker CPP decreases MAC of cyclopropane and sevoflurane by comparable amounts despite a 2.6-fold difference in their in vitro potencies as blockers of the NMDA receptor. In contrast, the decrease in MAC of hexafluorobenzene, 1,2,4-trifluorobenzene, and o-difluorobenzene correlates inversely with their in vitro potencies as blockers of the NMDA receptor.

 

Infusion of 8 µg · kg–1 · min–1 MK-801 decreased the concentration of etomidate associated with no movement from 21.0 ± 7.6 µg/mL (n = 7) to 10.2 ± 4.0 µg/mL (n = 4). This 51.4 ± 19.0% decrease was comparable to the 45.5 ± 4.2% decrease seen in our experiments with anesthetics not containing a benzene ring (Fig. 2; Table 2).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We hypothesized that administration of MK-801 or CPP would decrease the MAC of anesthetics that potently block NMDA receptors less than the MAC of anesthetics that minimally block NMDA receptors. The hypothesis rests on several observations and assumptions. First, MK-801 administration decreases the MAC of most anesthetics (Figs. 1–3). This implies the presence of ongoing transmission via NMDA receptors that can be blocked and whose blockade decreases anesthetic requirement. Second, administration of MK-801 produces a maximum decrease in MAC of 50% to 60% (Figs. 1 and 3). This indicates that actions on channels other than NMDA receptors must be present at MAC to cause immobility. Third, these observations suggest that immobility in the present study may result from three components: (A) an action of the anesthetic on channels other than NMDA receptors; (B) blockade of few/many/most NMDA receptors by the anesthetic; and (C) blockade of remaining unblocked NMDA receptors by MK-801 or CPP. Consider the implications of blockade of few versus most NMDA receptors by the anesthetic. If the anesthetic has blocked few NMDA receptors, then many are available for blockade by MK-801, and administration of MK-801 should decrease MAC. If the anesthetic has blocked most NMDA receptors, then few are available for blockade by MK-801, and administration of MK-801 should minimally decrease MAC; the requirement to act on channels other than those governed by NMDA receptors, would not change.

The data for aromatic compounds appear to confirm the hypothesis that the MAC of anesthetics that potently block NMDA receptors would be less affected by administration of MK-801 or CPP. (Tables 2 and 3, Figs. 2–4). MK-801 minimally decreases MAC for benzene, fluorobenzene, and o-difluorobenzene; aromatic anesthetics that most potently inhibit NMDA receptors in vitro. Pentafluorobenzene and hexafluorobenzene weakly block the NMDA receptor, and MK-801 infusion decreases the MAC of these compounds the most. P-difluorobenzene, 1,3,5,-trifluorobenzene, and 1,2,4-trifluorobenzene have intermediate effects on the NMDA receptor, and MK-801 infusion produces intermediate decreases in their MACs. Thus, these data for aromatic compounds would appear to indicate that the NMDA receptor mediates the immobility produced by anesthetics that are potent inhibitors of the NMDA receptor.

In contrast to the results with aromatic compounds, MK-801 and CPP considerably, and nearly equally affect the MAC of all other test anesthetics (Tables 2 and 3, Figs. 2–4). These include the clinically useful anesthetics cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, and sevoflurane, as well as the noble gas xenon. Such findings suggest that NMDA receptors do not mediate the capacity of most inhaled anesthetics, particularly conventional inhaled anesthetics, to produce immobility. The quantitative and qualitative similarity of the results with 8 µg · kg–1 · min–1 MK-801 and 530 µg · kg–1 · min–1 CPP for anesthetics that cover the range of in vitro depression of NMDA receptors by all conventional anesthetics suggests that the manner of blockade of such receptors does not influence the results or the conclusions there from.

The data illustrated in Figure 1 provide circumstantial evidence that the infusion rates of 8 and 32 µg · kg–1· min–1 MK-801 achieve maximum or near maximum in vivo blockade of NMDA receptors. For both isoflurane and xenon, infusion rates of up to 8 µg · kg–1 · min–1 steeply decreased MAC, but further increases in rate caused only modestly greater decreases in MAC. Indeed, doubling the infusion rate from 32 to 64 µg · kg–1 · min–1 does not further decrease MAC.

However, two observations suggest that infusion of 32 µg · kg–1 · min–1 MK-801 produces greater, more complete and more consistent blockade than infusion of 8 µg · kg–1 · min–1. With one exception (fluorobenzene), the greater infusion always produces a greater decrease in MAC (Table 2). It also produces an effect that correlates more steeply and consistently (note greater correlation coefficients) with the in vitro capacities of each anesthetic to block NMDA receptors (Figs. 2 and 3). This would be explained if the 8 µg · kg–1· min–1 produces only a partial blockade, one that might vary as a function of kinetics or degradation of MK-801. In contrast, complete blockade (as might be produced with the 32 µg · kg–1 · min–1 infusion) would be consistent regardless of kinetics or degradation.

Some findings in other models partially confirm and conflict with our findings for conventional anesthetics. Studies in the nematode C. Elegans suggest that NMDA mediates several anesthetic effects of nitrous oxide but not of volatile anesthetics such as isoflurane or halothane (24). However, none of the tests of anesthesia may be precisely parallel to MAC, and the maximum concentration of nitrous oxide applied was 70%, a concentration that may be too low to reveal all effects of nitrous oxide. More pertinent is the finding that knocking out the NMDA receptor {epsilon}1 subunit gene in mice does not decrease the MAC of sevoflurane (25), but does decrease the contribution of nitrous oxide to the MAC of sevoflurane (25). However, this work also found that the mice with the knockout resisted the duration of effects of propofol, pentobarbital, diazepam and midazolam, compounds thought to depend upon the GABAA receptor. The authors also had found this effect for ketamine (26), an anesthetic that is thought to act on the NMDA receptor to produce anesthesia. The authors interpreted this finding as suggesting that the NMDA receptor mediates the effects of all these compounds. An alternative notion might be that the knockout of the gene produced compensatory changes that make any interpretation difficult to apply.

The notion that NMDA receptors do not mediate the immobility produced by conventional anesthetics is consistent with the effects of such anesthetics on temporal summation. Temporal summation is the cumulative effect of a succession of repeated stimuli presented at sufficiently close intervals (27). Stated another way, a shortening of the intervals between stimuli increases the collective stimulation perceived by the central nervous system and is more likely to provoke a response. In vitro, blocking NMDA receptors blocks temporal summation, indicating that NMDA receptors lie in the pathway that mediates temporal summation (28). These observations suggest that persistence of temporal summation during anesthetic administration reflects intact NMDA receptor function. The present study and previous studies with isoflurane suggest that approximately 40%-60% of the generation of movement evoked by noxious stimulation (MAC) depends on interstimulus interval, suggesting the persistence of temporal summation and transmission via NMDA pathways. Strengthening this interpretation, if temporal summation persists, then administration of the NMDA blocker MK-801 should abolish summation, and that is what appears to occur (29). Also consistent with the interpretation that isoflurane does not block temporal summation, electrophysiologic studies of neuronal wind-up show that temporal summation can occur during anesthesia (30).

Results from the etomidate study further support the hypothesis that NMDA receptors minimally mediate or do not mediate the capacity of conventional inhaled anesthetics to produce immobility. As noted earlier, etomidate exerts its anesthetic effects primarily through its capacity to enhance the response of GABAA receptors to GABA. It does not depend on blockade of NMDA receptors to achieve anesthesia. Nonetheless, as with conventional inhaled anesthetics having a wide range of in vitro capacities to block the NMDA receptor, administration of 8 µg · kg–1 · min–1 MK-801 produced a 51.4 ± 19.0% decrease in the MAC of etomidate, a decrease comparable to the 45.5 ± 4.2% decrease seen for conventional anesthetics (Fig. 2; Table 2). If such conventional anesthetics act, in part, by blocking NMDA receptors, then we would have anticipated a smaller decrease from 8 µg · kg–1 · min–1 MK-801 administration with conventional anesthetics than with etomidate.

Thus, the evidence from the present study is compatible with the notion that NMDA receptors do not mediate the immobility produced by conventional inhaled anesthetics. However, other explanations of our data may allow a different interpretation. For example, several of the test anesthetics inhibit the NMDA receptor by 50–70% at MAC, but this equal inhibition does not translate to equal sensitivities to MK-801 (i.e., note the considerable differences between the aromatic and conventional anesthetics at the far right in Figs. 2 and 3). How can anesthetics equally inhibit the NMDA receptor and not have equal sensitivity to MK-801? Part of the answer might relate to multiple receptor effects of the tested anesthetics, and different anesthetic actions at the network level. And inhaled anesthetics may not have the same effects in vivo as they do in a standard in vitro assay such as we applied in this report. Thus, it may be too simplistic to correlate anesthetic effects on a receptor to a behavioral effect (immobility). In addition, the efficacy of MK-801 relates to the amount of ongoing (basal) glutamatergic transmission. MK-801 produces a use-dependent non-competitive block of the NMDA channel, and its effect is long-lasting. And anesthetics may diminish the binding of MK-801 to NMDA receptors (14). Finally, MK-801 may be a "dirty" blocker, potently affecting other receptors such as dopamine (31). In that regard, we are comforted by the parallel results obtained with CPP, and by the results of an ancient study that suggest that elimination of all central nervous system catecholamines (including dopamine) decreases MAC by a mere 30% for halothane (32) and not at all for cyclopropane (33).

The pharmacological limitations noted above might have affected the present results in an unknown way. Furthermore, as part of our data analysis, we separated the aromatic anesthetics from the non-aromatic clinical anesthetics because there was a clear difference between the results for these two groups. One could argue, however, that because there was no a priori reason for this separation, all the anesthetics tested should have been treated as one group. Such an analysis results in no significant correlation between NMDA receptor inhibition and the MAC-sparing effect of MK-801, a finding consistent with, but not identical to, our primary conclusion.

We cannot provide a definitive explanation for the difference in results for conventional inhaled anesthetics and the results for aromatic compounds, but we might speculate on the basis for such a difference. Conventional wisdom suggests that inhaled anesthetics block movement primarily by an action on the spinal cord. However, the evidence for this comes from studies of only two conventional anesthetics, isoflurane (16,34) and halothane (35). We assume that these results apply broadly, but perhaps not. Perhaps all the conventional anesthetics in the present study do act on the cord. But aromatic compounds might be like propofol (another compound with a benzene ring) that probably acts on cerebral receptors to produce anesthesia. Blockade of cerebral NMDA receptors might underlie the differential effect of MK-801 on aromatic compounds.

In summary, we tested whether NMDA receptors are important to the immobility produced by inhaled anesthetics. We reasoned that if they are important then the effect of a blocker of NMDA receptors should produce different changes in MAC as a function of the in vitro capacity of the anesthetics to inhibit the receptor (less with those anesthetics that inhibit most). We found this relationship for aromatic compounds but not for conventional inhaled anesthetics. Thus, the present results, and the results in the sister reports that accompany the present report (13,29), provide evidence for the hypothesis that the NMDA receptor does not mediate the immobility produced by conventional inhaled anesthetics. Further evidence may be required to certify that NMDA receptors are not prime mediators of the immobility produced by inhaled anesthetics. For example, engineering of an animal that responds normally to glutamate but whose NMDA receptors are not blocked (or are less blocked) by inhaled anesthetics might be used to supply such evidence. If the hypothesis is correct, the MAC of such an animal should not differ from the MAC for its wild-type control.


   Footnotes
 
Dr. Eger is a paid consultant to Baxter Healthcare Corp. Baxter Healthcare Corp. donated the desflurane and isoflurane used in these studies.

Accepted for publication February 9, 2006.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press