This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dutton, R. C. Articles by Eger, E. I. Search for Related Content PubMed PubMed Citation Articles by Dutton, R. C. Articles by Eger, E. I., II Related Collections Mechanisms Pharmacology

---

ANESTHETIC PHARMACOLOGY

Do N-Methyl-d-Aspartate Receptors Mediate the Capacity of Inhaled Anesthetics to Suppress the Temporal Summation that Contributes to Minimum Alveolar Concentration?

Robert C. Dutton, MD^*, Michael J. Laster, DVM^*, Yilei Xing, MD^*, James M. Sonner, MD^*, Douglas E. Raines, MD, Ken Solt, MD, and Edmond I. Eger, II, MD^*

*Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California; Department of Anaesthesia and Critical Care, Massachusetts General Hospital, and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Robert C. Dutton, MD, Department of Anesthesia, S-455, University of California, San Francisco, California 94143-0464. Address e-mail to dutton20{at}comcast.net.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of inhaled anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by inhaled anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
How inhaled anesthetics produce immobility remains largely unknown. Although in vitro studies find that effects of inhaled anesthetics on numerous receptors provide plausible explanations for anesthesia, most of these receptors now appear to be unlikely targets of anesthetic action (1). However, the N-methyl-d-aspartate (NMDA) receptor remains a promising candidate (1). The NMDA receptor conducts excitatory synaptic signaling and is involved in neuronal plasticity (2,3). Anesthetic disruption of these processes (1,4–12) could contribute to the production of the immobility that forms the basis for the standard definition of anesthetic potency, MAC (the minimum alveolar concentration of an inhaled anesthetic required to suppress movement in 50% of subjects in response to supramaximal noxious stimulation).

Temporal summation, a form of neuronal plasticity, is the cumulative effect of repetitive stimulation. We reported that temporal summation underlies part of the movement suppressed at MAC during isoflurane anesthesia (4). We found that increased stimulus frequency increased the concentrations of isoflurane needed to suppress movement, and that MK801, an NMDA receptor antagonist, blocked this effect (i.e., in the presence of MK801 the concentration of isoflurane required to block response to a single stimulus did not differ from the concentration required to block the response to multiple stimuli). These findings suggest that NMDA receptors contribute to the temporal summation involved in the generation of complex (purposeful) movement to noxious stimuli. Thus, some transmission of NMDA receptor-mediated currents continues during isoflurane anesthesia, at least at concentrations less than MAC. The present study asked whether suppression of those currents contributed to part of the immobility at MAC.

Inhaled anesthetics differ in their ability to suppress currents in NMDA receptors expressed in Xenopus oocytes. For example, 1.0 MAC concentrations of halothane, isoflurane, and xenon decrease NMDA receptor mediated currents by 24%, 28%, and 57%, respectively (13,14). If blockade of NMDA receptor activity produces immobility, then inhaled anesthetics having greater ability to suppress NMDA receptor action would be expected to produce greater suppression of the temporal summation NMDA receptor component involved in immobility. Not doing so would suggest that NMDA receptor blockade does not mediate immobility.

To compare in vitro NMDA receptor blocking action with temporal summation effects on immobility, we selected inhaled anesthetics having a range of NMDA receptor-suppressing actions (13,14). We measured the effect of these anesthetics on temporal summation by applying brief electrical pulses of varying interstimulus intervals (ISIs) to the tails of rats (4). The ISI is 1 divided by the frequency of the pulses. To determine the importance of NMDA receptors in temporal summation, a role we term the NMDA receptor component, we administered MK801 to other rats receiving the anesthetics and ISI pulses (4). The present results indicate that suppression of NMDA receptors may contribute to the capacity of some, but not most, inhaled anesthetics to produce immobility.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
With approval of the Committee on Animal Research of the University of California, San Francisco, we studied 82 male (Crl:CD(SD)BR) rats weighing 300–450 g obtained from Charles River Laboratories (Hollister, CA). Each rat was used in only one experiment, 6 rats for each anesthetic with MK801 infusion and 8 rats for each anesthetic without MK801. Rats were housed in rooms with daily cycles of 12 h of light and 12 h of dark and had water and standard rat chow ad libitum. At least 24 h before the studies in which MK801 was given during isoflurane anesthesia, PE10 IV catheters were placed in the right jugular vein, and the open end of the catheter was tunneled to the ear where it exited and could be accessed.

Halothane was obtained from Halocarbon (River Edge, NJ), isoflurane from Baxter Heathcare Corporation (New Providence, NJ), hexafluorobenzene and o-difluorobenzene from Sigma-Aldrich (St. Louis, MO), and xenon from Airgas Incorporated (Radnor, PA).

Halothane, isoflurane, hexafluorobenzene, and o-difluorobenzene concentrations required to suppress movement at different ISIs (crossover concentrations) were determined concurrently in two or three rats enclosed in individual clear plastic cylinders. Three pairs of platinum needle electrodes (type E2, Grass Instruments, Quincy, MA) were placed in the tail, a rectal temperature probe was inserted, and the connecting wires, temperature probe, tail of the rat, and catheter (during MK801 infusions) 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 flow of 1 L/min of oxygen and anesthetic vapor was delivered per cylinder, and the exiting gases were scavenged.

For xenon, crossover concentrations were determined in two rats concurrently. Each rat was placed in a clear plastic tube closed at the distal end with a rubber stopper pierced with several holes that allowed the free flow of gases. A rectal temperature probe and the rat’s tail were drawn through two of these holes. Three pairs of platinum needle electrodes were placed 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 to an infusion pump. The deadspace volume of the IV and connecting catheters for all studies equaled approximately 17 µL. After flushing with oxygen to produce an exiting oxygen concentration exceeding 95%, the chamber was sealed and the pressure brought to one atm. Xenon then was introduced.

Crossover concentrations were determined for each in a series of temporally graded electrical pulses (50 V trains of 0.5 ms square-waves having interstimulus intervals of 10, 3, 1, 0.3, or 0.1 s) (BIOPAC Systems Inc., Santa Barbara, CA). A train of stimuli of the selected ISI was delivered through the most distal pair of electrodes for 120 s for the 10 s and 60 s for all the other ISI pulses, or until the animal moved, whichever occurred sooner. After delivering a train of one ISI, a period of 2 min was allowed before delivering the next train. The trains were delivered in order of descending (shorter) ISIs. When a train produced a latency <10 s, trains with shorter ISIs were omitted (4). After achieving a concentration in which a train of 0.1-s ISI pulses no longer produced movement, in some animals the train was applied to a more proximal set of electrodes. MAC was determined by applying an alligator clip oscillated at approximately ±45° and 1 Hz for 60 s, or until the animal moved (15,16). The MAC for xenon requires a high pressure chamber and because the chamber precludes the use of an alligator clip, MACs for xenon and other anesthetics were also determined applying equivalent electrical stimulation as defined by Laster et al. (17,18), here, the 0.1-s ISI train. For all anesthetics, the concentration was increased to a step just less than the concentration required to produce immobility to the 10-s ISI train. After an equilibration period of 20 min (hexafluorobenzene), 30 min (xenon, isoflurane, and o-difluorobenzene), or 40 min (halothane) (14), the series of test stimuli were applied and animals observed for complex (purposeful) movement responses or immobility. After completing one series, the anesthetic concentration was increased by 10% to 20% of the nominal MAC and the series of stimuli repeated for trains that had previously produced movement. Similar step increases, equilibration, and application of test stimuli were applied until a concentration was achieved at which animals did not move to any stimulus. This procedure provided concentrations for move and no move responses for each stimulus train in each rat.

For MK801 studies, 2.5 or 50 µg · kg^–1 · min^–1 MK801 (Sigma-Aldrich, Inc., St. Louis, MO) was administered through the previously placed IV catheter. Two animals were studied concurrently. Infusions of MK801 began with an initial loading dose of solution sufficient to clear the catheter and addition of the equivalent of what would be infused in the course of approximately 10 min of infusion at the target rate.

The rectal temperature was maintained at approximately 37°C by applying a heat lamp or ice as needed.

For studies of volatile anesthetics, the concentration in a representative cylinder was continuously monitored with an infrared analyzer (Capnomac II or Ohmeda RGM 5250; Datex, Helsinki, Finland). Volatile anesthetic concentrations after stimulation were measured with a flame ionization detector gas chromatograph (Gow-Mac 750 Instrument Corp, Bethlehem, PA) as previously described (14). The xenon concentration before and after stimulation was measured with a thermal conductivity detector gas chromatograph (Gow-Mac 580, Bethlehem, PA) and corrected to a partial pressure by accounting for the total pressure in the pressure chamber, as previously described (14). For all studies, the concentration determined by gas chromatography was used as the defining concentration.

MAC values were separately determined by tail clamp and 0.1-s ISI pulses and were taken as the midpoint of the concentrations just permitting and suppressing the response to each. For temporally graded stimulation studies, the MAC fraction at a crossover for each ISI train was calculated as the midpoint of the concentrations just permitting and suppressing the response for each animal divided by the crossover concentration to the 0.1-s ISI train, for that group. MAC fraction means ± sd were calculated. For hexafluorobenzene and o-difluorobenzene, the midpoint concentrations were converted to MAC values, as previously described (19).

The slope of temporal summation was calculated by linear regression of individual values in a group, as the change in MAC fraction with decrease in ISI (MAC fraction/-log[ISI]); values ± se) were calculated (StatView 4.5; SAS Institute Inc., Cary, NC). The temporal summation NMDA receptor component of slope was calculated as the difference between slope without MK801 minus the slope during MK801 (2.5 µg · kg^–1 · min^–1), difference ± se. This component was also expressed as a percentage decrease in MAC after multiplying the slope difference by the denominator of the slope, which in all cases equaled 2 (e.g., log [0.1 s] - log [10 s]), converting the slope to a MAC fraction. The nontemporal summation NMDA receptor component of MAC was calculated by subtracting the temporal summation NMDA receptor component from the total NMDA receptor component of MAC revealed by MK801 infusion during MAC equivalent stimuli (0.1-s pulses). The non-NMDA receptor component of slope was taken as the slope during MK801 (2.5 µg · kg^–1 · min^–1). Student’s t-tests were used to compare slopes and concentrations, and a value of P < 0.05 was regarded as significant for all comparisons.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The anesthetics we used differ in their capacities to suppress currents in NMDA receptors expressed in Xenopus oocytes. Hexafluorobenzene and halothane produce the least suppression, 13% and 24%, isoflurane more suppression, 28%, and o-difluorobenzene and xenon the greatest suppression, 51% and 57%, respectively (13,14).

The concentrations required to achieve immobility to tail clamp, i.e., MAC, for hexafluorobenzene, halothane, isoflurane, and o-difluorobenzene were similar to those previously reported (14,18–21) (Table 1). The crossover concentrations required to achieve immobility to trains of 0.1-ISI pulses were similar to those for the MAC determined by tail clamp (Table 1), and for xenon they were similar to those reported for 50-Hz pulses (14,18). For consistency, the MAC fractions of all anesthetics were calculated based on the MAC provided by the 0.1-s ISI trains.

For all anesthetics, crossover concentrations increased as the ISI decreased (P < 0.05) (Fig. 1). Hexafluorobenzene produced a result similar to that produced by halothane.

View larger version (29K): [in this window] [in a new window]   Figure 1. Effect of stimulus interstimulus interval (ISI) on crossover concentrations for each ISI during halothane, isoflurane, xenon, and o-difluorobenzene. Crossover concentrations increase as the ISI decreases during each anesthetic. Adding MK801 (2.5 µg · kg–1 · min–1) markedly suppresses slopes during halothane and isoflurane, modestly during xenon, and does not suppress the slope during o-difluorobenzene. The results for hexafluorobenzene are similar to those for halothane. For isoflurane, the solid lines show current results and the dotted lines show previously reported results (4).

The slopes reflecting temporal summation for o-difluorobenzene and xenon were less steep than for isoflurane (P < 0.05) (Table 2). Otherwise the slopes did not differ significantly.

Infusion of MK801 at 2.5 µg · kg^–1 · min^–1 markedly decreased the slope of temporal summation for hexafluorobenzene, halothane, and isoflurane (P < 0.05), revealing temporal summation NMDA receptor components of 21% ± 4%, 29% ± 5%, and 24% ± 5% of MAC (mean ± se), respectively (P < 0.05 for each) (Table 2). In contrast, this MK801 infusion did not significantly decrease the slope for o-difluorobenzene and xenon, –1% ± 9% and 8% ± 5%, respectively (neither significant), indicating that these anesthetics had already suppressed the NMDA receptor component of temporal summation (Table 2). Infusion of MK801, 50 µg · kg^–1 · min^–1, during isoflurane and xenon administration did not additionally decrease the already almost flat temporal summation curves (no significant change), indicating that MK801 at 2.5 µg · kg^–1 · min^–1 produced a maximum decrease in slope for these anesthetics.

The results during MK801 infusion suggest two slope components of temporal summation, a non-NMDA receptor component seen during MK801 infusion and a NMDA receptor component revealed as the difference between slopes, that is, as the slope without MK801 minus the slope during MK801, 2.5 µg · kg^–1 · min^–1, (Table 2). The NMDA receptor component reflects NMDA receptor function remaining intact during an anesthetic (14).

The anesthetics produced a range of crossover concentrations (as fractions of MAC) to the 10-s ISI stimuli (Fig. 1). Consistent with the relatively shallow slopes for o-difluorobenzene and xenon, the crossover concentrations to the 10 s stimuli differed less from MAC than did the crossover concentrations for hexaflurorobenzene, halothane, and isoflurane. Anesthetics with the least in vitro potencies as blockers of NMDA receptors had the smallest crossover concentrations and those with greater potencies had larger crossover concentrations. A larger crossover concentration would suggest a lesser NMDA receptor contribution to temporal summation.

MK801 (2.5 µg · kg^–1 · min^–1) modestly decreased the crossover concentrations for the 10-s ISI stimuli for hexafluorobenzene, halothane, isoflurane, and o-difluorobenzene, and markedly decreased the crossover concentrations for the 10-s ISI stimuli for xenon (Fig. 1, Table 3). The results reflect the nontemporal summation NMDA component revealed as the difference between crossover concentrations to 10-s ISI stimuli (Table 3). These components are also expressed as percentage decreases in MAC (Table 3). The nontemporal summation NMDA receptor component of MAC during MK801 (2.5 µg · kg^–1 · min^–1) was more formally calculated by subtracting the temporal summation NMDA receptor component (Table 2) from the decrease in crossover concentrations to 0.1-s pulse components, yielding results not different from those in Table 3 (data not shown).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We find that crossover concentrations increase for all anesthetics as the ISI decreases, indicating that temporal summation defined by movement in response to noxious stimulation persists up to MAC with inhaled anesthetics that differ widely in their in vitro capacity to block NMDA receptors. Furthermore, the extent of temporal summation varies among the anesthetics.

The results also indicate that a small infusion of MK801 (2.5 µg · kg^–1 · min^–1) suppresses temporal summation for some, but not all, anesthetics. Coupled with the concept that the NMDA receptor component is revealed as MK801-induced suppression of slope, that is, as the difference between the slopes with and without MK801, these results indicate that a temporal summation NMDA receptor component is present during hexafluorobenzene, halothane, and isoflurane but not o-difluorobenzene or xenon (Table 2).

A 20-times larger infusion (50 µg · kg^–1 · min^–1) does not further decrease the slope during isoflurane or xenon. We did not test the larger MK801 infusion during halothane or o-difluorobenzene because the infusion of MK801 (2.5 µg · kg^–1 · min^–1) produced a flat slope during halothane (not different from zero) and during o-difluorobenzene the decrease in MAC with MK801 (32 µg · kg^–1 · min^–1) (14) was not different than with MK801 (2.5 µg · kg^–1 · min^–1), 11% ± 10% and 14% ± 6%, respectively, indicating that the maximal slope reduction had been reached during the smaller MK801 infusion with these anesthetics. So, we submit that the results during MK801 (2.5 µg · kg^–1 · min^–1) reveal the temporal summation NMDA receptor component involved in immobility.

There is also a portion of temporal summation that appears to be independent of NMDA receptor activity, as evidenced by the continuing presence of a slope for anesthetics during infusion of MK801 and the finding that the larger infusion rate of MK801 did not cause a further decrease in slope during isoflurane or xenon. The non-NMDA receptor component of temporal summation is intriguing, but we can say little about it at this time. For ISI pulses shorter than 1 s, short-term plasticity processes such as facilitation may be involved (9,22). The large non-NMDA receptor component during o-difluorobenzene was unexpected. Pilot studies with benzene (data not shown) also suggest a large non-NMDA receptor component, as evidenced by a temporal summation slope similar to that of o-difluorobenzene and a minimal MAC-sparing effect of MK801 during benzene (14).

Is anesthetic-induced suppression of temporal summation relevant to MAC? Previously, we found that the differences between crossover concentrations for 0.1-s and 10-s ISI stimuli (e.g., an alternative measure of slope) did not change as stimulus voltage increased over 0.0 to nearly 1.0 MAC isoflurane (4). Similar results were reported for studies in humans (23). This indicates that isoflurane does not dose-dependently depress the slope of temporal summation and, thus, that isoflurane has little or no effect on the temporal summation NMDA receptor component. Because hexafluorobenzene, halothane, and isoflurane similarly affect NMDA receptors in vitro and similarly affect the NMDA receptor component of temporal summation and the crossover concentrations to the 10 s ISI stimuli, we suggest that their actions on NMDA receptors are not important to their production of immobility. In contrast, the marked to complete suppression of our surrogate measures of NMDA receptor components by xenon and o-difluorobenzene indicate that NMDA receptor suppression may be important for the production of immobility by these anesthetics.

The effects of MK801 on both the slope of the ISI curves and the concentration of anesthetic needed to suppress movement at long ISIs suggest that the amount of NMDA receptor required to produce MAC-related effects needs to exceed a threshold, that is, to overcome a margin of safety (24). Addition of MK801 (2.5 µg · kg^–1 · min^–1) produced only small decreases in crossover concentrations to 10-s ISI pulses with hexafluorobenzene, halothane, and isoflurane. This is consistent with production of limited NMDA receptor blockade, with the impairment produced being within a margin of safety at this stimulus interval. Evident at greater frequencies, the addition of MK801 (2.5 µg · kg^–1 · min^–1) extended blockade beyond the margin of safety required for temporal summation and thereby decreased the anesthetic concentration that produced immobility.

The greater sensitivity of temporal summation versus nontemporal summation NMDA receptor components to blockade may be applied to the results of the larger MK801 infusion (32 µg · kg^–1 · min^–1) administered by Eger et al. (14). This infusion produced decreases in MAC during hexafluorobenzene, halothane, isoflurane, and xenon (14) 11% to 38% greater than those we found for MK801 (2.5 µg · kg^–1 · min^–1), although no additional decrease was observed during o-difluorobenzene. Because the temporal summation NMDA receptor component had already been revealed by the 2.5 µg · kg^–1 · min^–1 infusion, we suggest that this additional decrease was a result of further revealing of the nontemporal summation NMDA receptor component.

Our study of crossover concentrations during 10-s ISI stimuli and MK801 suggests that xenon, markedly, but halothane and isoflurane, minimally, suppressed NMDA receptors during these stimuli. These results are consistent with electrophysiologic studies of excitatory synaptic transmission that commonly use long ISI electrical stimuli (8,10,12). Xenon, but not isoflurane, strongly suppressed NMDA receptor mediated synaptic transmission in hippocampal cells (11), and although halothane and isoflurane suppressed NMDA receptor-mediated synaptic transmission in hippocampal slices, it was the depression of presynaptic processes, not NMDA receptor blockade, that accounted for most of the effect (9,10).

Our study approach has some limitations. We tested the effects of only a few anesthetics, although these anesthetics ranged widely in their in vitro effects on NMDA receptors and thus would be expected to be broadly representative. We primarily applied a single dose of MK-801, but that dose was shown, as described in the companion article, (14) to have a major effect on the MAC of most inhaled anesthetics. And finally, we studied inspired rather than end-tidal anesthetic concentrations. However, because all rats were treated identically, that should not compromise the comparative aspects of our results.

In summary, blockade of NMDA receptors provides two MAC-related aspects. The first is more sensitive, stimulus-frequency dependent, and related to temporal summation. The second is relatively stimulus-frequency independent and related to nontemporal summation processes, perhaps excitatory synaptic transmission. Halothane, isoflurane, and hexafluorobenzene do not appear to suppress either aspect. Xenon appears to suppress the temporal summation aspect and o-difluorobenzene to suppress both aspects. Thus, NMDA receptor blockade may contribute to the MAC produced by some, but not all, inhaled anesthetics. We conclude that the impairment of NMDA receptors may explain the action of a few inhaled anesthetics as defined by MAC, but that for most anesthetics (particularly the ones used everyday) may have little or no relevance to MAC.

	Footnotes

 
Accepted for publication January 12, 2006.

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

Supported, in part, by NIH grant 1POIGM47818.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar concentration. Anesth Analg 2003;97:718–40.[Abstract/Free Full Text]
2. Kandel ER, Siegelbaum SA. Synaptic integration. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of neural science, 4th ed. New York: McGraw-Hill, 2000:207–27.
3. Banke TG, Traynelis SF. Activation of NR1/NR2B NMDA receptors. Nature Neuroscience 2003;6:144–52.[Web of Science][Medline]
4. Dutton RC, Zhang Y, Stabernack CR, et al. Temporal summation governs part of the minimum alveolar concentration of isoflurane anesthesia. Anesthesiology 2003;98:1372–7.[Web of Science][Medline]
5. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 1991;44:293–9.[Web of Science][Medline]
6. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31–9.[Medline]
7. Wang M, Rampil IJ, Kendig JJ. Ethanol directly depresses AMPA and NMDA glutamate currents in spinal cord motor neurons independent of actions on GABA_A or glycine receptors. J Pharmacol Exper Ther 1999;290:362–7.[Abstract/Free Full Text]
8. Cheng G, Kendig JJ. Enflurane directly depresses glutamate AMPA and NMDA currents in mouse spinal cord motor neurons independent of action on GABA_A or glycine receptors. Anesthesiology 2000;93:1075–84.[Web of Science][Medline]
9. MacIver MB, Mikulec AA, Amagasu SM, Monroe F. Volatile anesthetics depress glutamate transmission via presynaptic actions. Anesthesiology 1996;85:823–34.[Web of Science][Medline]
10. Nishikawa K, MacIver MB. Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses. Anesthesiology 2000;92:228–36.[Web of Science][Medline]
11. de Sousa LM, Dickinson R, Lieb WR, Franks NP. Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000;92:1055–66.[Web of Science][Medline]
12. Perouansky M, Baranov D, Salman M, Yaari Y. Effects of halothane on glutamate receptor-mediated excitatory postsynaptic currents: A patch-clamp study in adult mouse hippocampal slices. Anesthesiology 1995;83:109–19.[Web of Science][Medline]
13. Solt K, Eger EI II, Raines DE. Differential modulation of N-methyl-d-aspartate receptors by structurally diverse general anesthetics. Anesth Analg 2006;102: ? in Press.
14. Eger EI II, Liao M, Laster MJ, et al. Do NMDA receptors mediate the capacity of inhaled anesthetics to produce immobility? Anesth Analg 2006;102 1412–8.[Abstract/Free Full Text]
15. Eger EI II, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration; a standard of anesthetic potency. Anesthesiology 1965;26:756–63.[Web of Science][Medline]
16. Rampil IJ. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 1994;80:606–10.[Web of Science][Medline]
17. Laster MJ, Liu J, Eger EI II, Taheri S. Electrical stimulation as a substitute of the tail clamp in the determination of anesthetic potency. Anesth Analg 1993;76:1310–2.[Web of Science][Medline]
18. Koblin DD, Fang Z, Eger EI II, et al. Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics). Anesth Analg 1998;87:419–24.[Abstract/Free Full Text]
19. Fang Z, Sonner J, Laster MJ, et al. Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis. Anesth Analg 1996;83:1097–104.[Abstract]
20. Eger EI II, Koblin DD, Laster MJ, et al. Minimum alveolar anesthetic concentration values for the enantiomers of isoflurane differed minimally. Anesth Analg 1997;85:188–92.[Abstract]
21. Vitez TS, White PF, Eger EI II. Effects of hypothermia on halothane MAC and isoflurane MAC in the rat. Anesthesiology 1974;41:80–1.[Web of Science][Medline]
22. Zucker BM. Short-term plasticity. Annu Rev Physiol 2002;64:355–405.[Web of Science][Medline]
23. Petersen-Felix S, Arendt-Nielsen L, Bak P, et al. The effects of isoflurane on repeated nociceptive stimuli (central temporal summation). Pain 1995;64:277–81.
24. Waud DR, Waud BE. In vitro measurement of margin of safety of neuromuscular transmission. Am J Physiol 1975;229:1632–4.[Abstract/Free Full Text]

This article has been cited by other articles:

				A. B. Petrenko, T. Yamakura, T. Kohno, K. Sakimura, and H. Baba Reduced Immobilizing Properties of Isoflurane and Nitrous Oxide in Mutant Mice Lacking the N-Methyl-d-Aspartate Receptor GluR{epsilon}1 Subunit Are Caused by the Secondary Effects of Gene Knockout Anesth. Analg., February 1, 2010; 110(2): 461 - 465. [Abstract] [Full Text] [PDF]

				J. C. Sewell, D. E. Raines, E. I. Eger II, M. J. Laster, and J. W. Sear A Comparison of the Molecular Bases for N-Methyl-d-Aspartate-Receptor Inhibition Versus Immobilizing Activities of Volatile Aromatic Anesthetics Anesth. Analg., January 1, 2009; 108(1): 168 - 175. [Abstract] [Full Text] [PDF]

				E. I. Eger II, D. E. Raines, S. L. Shafer, H. C. Hemmings Jr, and J. M. Sonner Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? Anesth. Analg., September 1, 2008; 107(3): 832 - 848. [Abstract] [Full Text] [PDF]

				A. Yao, J. Kim, R. Atherley, S. L. Jinks, E. Carstens, S. Shargh, A. Sulger, and J. F. Antognini The Effects of Aromatic Anesthetics on Dorsal Horn Neuronal Responses to Noxious Stimulation Anesth. Analg., June 1, 2008; 106(6): 1759 - 1764. [Abstract] [Full Text] [PDF]

				R. C. Dutton, J. M. Cuellar, E. I. Eger II, J. F. Antognini, and E. Carstens Temporal and Spatial Determinants of Sacral Dorsal Horn Neuronal Windup in Relation to Isoflurane-Induced Immobility Anesth. Analg., December 1, 2007; 105(6): 1665 - 1674. [Abstract] [Full Text] [PDF]

				K. P. Ng and J. F. Antognini Isoflurane and Propofol Have Similar Effects on Spinal Neuronal Windup at Concentrations that Block Movement Anesth. Analg., December 1, 2006; 103(6): 1453 - 1458. [Abstract] [Full Text] [PDF]

				R. C. Dutton, M. J. Laster, Y. Xing, J. M. Sonner, D. E. Raines, K. Solt, and E. I. Eger II Do N-Methyl-d-Aspartate Receptors Mediate the Capacity of Inhaled Anesthetics to Suppress the Temporal Summation that Contributes to Minimum Alveolar Concentration? Anesth. Analg., May 1, 2006; 102(5): 1412 - 1418. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dutton, R. C. Articles by Eger, E. I. Search for Related Content PubMed PubMed Citation Articles by Dutton, R. C. Articles by Eger, E. I., II Related Collections Mechanisms Pharmacology