Skip Navigation LinksHome > April 2000 - Volume 92 - Issue 4 > Contrasting Synaptic Actions of the Inhalational General Ane...
Anesthesiology:
Laboratory Investigations

Contrasting Synaptic Actions of the Inhalational General Anesthetics Isoflurane and Xenon

de Sousa, Sara L. M. Ph.D.*; Dickinson, Robert Ph.D.*; Lieb, William R. Ph.D.; Franks, Nicholas P. Ph.D.

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: The mechanisms by which the inhalational general anesthetics isoflurane and xenon exert their effects are unknown. Moreover, there have been surprisingly few quantitative studies of the effects of these agents on central synapses, with virtually no information available regarding the actions of xenon.
Methods: The actions of isoflurane and xenon on γ-aminobutyric acid–mediated (GABAergic) and glutamatergic synapses were investigated using voltage-clamp techniques on autaptic cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks.
Results: Isoflurane exerts its greatest effects on GABAergic synapses, causing a marked increase in total charge transfer (by approximately 70% at minimum alveolar concentration) through the inhibitory postsynaptic current. This effect is entirely mediated by an increase in the slow component of the inhibitory postsynaptic current. At glutamatergic synapses, isoflurane has smaller effects, but it nonetheless significantly reduces the total charge transfer (by approximately 30% at minimum alveolar concentration) through the excitatory postsynaptic current, with the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor–mediated components being roughly equally sensitive. Xenon has no measurable effect on GABAergic inhibitory postsynaptic currents or on currents evoked by exogenous application of GABA, but it substantially inhibits total charge transfer (by approximately 60% at minimum alveolar concentration) through the excitatory postsynaptic current. Xenon selectively inhibits the NMDA receptor–mediated component of the current but has little effect on the AMPA/kainate receptor–mediated component.
Conclusions: For both isoflurane and xenon, the most important targets appear to be postsynaptic. The authors’ results show that isoflurane and xenon have very different effects on GABAergic and glutamatergic synaptic transmission, and this may account for their differing pharmacologic profiles.
ALTHOUGH it has been widely accepted for many years that inhalational general anesthetics most probably act at synapses, 1 there have been surprisingly few quantitative studies of the effects of these drugs on central synaptic transmission (for a review see Pocock and Richards 2). What has emerged from the work performed so far is a picture of some complexity, with contradictory conclusions drawn regarding both the extent to which synaptic transmission is affected 3,4 and, in some cases, whether particular classes of synapse are inhibited or potentiated. 5–9 Nonetheless, a consensus is developing that inhalational anesthetics generally depress excitatory synapses 10,11 and potentiate inhibitory synapses, 5,12 but there is little agreement about either the molecular targets involved or which of these effects is the most important for any given anesthetic. This is true even for the most widely used agents, such as isoflurane, and for a number of recently introduced anesthetics (e.g., desflurane and sevoflurane). For the anesthetic gas xenon, which is being evaluated for routine surgical use, there is, other than a preliminary report from our laboratory, 13 essentially no information regarding molecular mechanisms.
For much of the previous work regarding the synaptic effects of inhalational anesthetics, brain slices have been used. These preparations maintain some of the native circuitry intact but have the concomitant difficulty of disentangling direct effects on particular synapses from indirect effects mediated by complex neuronal pathways. In addition, the problems encountered by several workers in handling highly volatile general anesthetics, in terms of evaporative losses and proper accounting for the temperature dependence in animal potencies, 14 has led to considerable uncertainties about whether the various synaptic effects described occur at clinically relevant concentrations.
These problems can be largely circumvented using the “microisland” culture technique, in which phenotypically identical populations of excitatory and inhibitory synapses can be studied in isolated neurons, 15–17 with volatile or gaseous anesthetics being rapidly applied at defined concentrations in aqueous solution. This approach has been used to elucidate the effects of nitrous oxide on glutamatergic and γ-aminobutyric acid–mediated (GABAergic) synapses in hippocampal neurons. 18 In the study reported herein, we followed similar protocols to investigate the actions of the widely used volatile anesthetic isoflurane and the “inert” gas xenon. These two inhalational agents have very different pharmacologic profiles (e.g., isoflurane causes a substantial degree of cardiovascular depression with little analgesia; xenon has little or no effect on the cardiovascular system but confers profound analgesia), and it is possible that these differences originate from differential effects on synaptic transmission.
Back to Top | Article Outline

Materials and Methods

This study conforms to the United Kingdom Animals (Scientific Procedures) Act of 1986.
Back to Top | Article Outline
Culturing Hippocampal Neurons
Hippocampal neurons were grown in culture using the methods described previously. 15–17 Briefly, hippocampi from Sprague-Dawley rats (postnatal days 1–3) were dissected, roughly sliced, and agitated in a papain-containing solution (20 U/ml) for 30 min at 37°C. After washing with enzyme-free solution, the tissue was gently triturated with a fire-polished Pasteur pipette, and the cells were plated out at a density of 8–10 × 104 cells/ml and cultured (95% air–5% CO2) at 37°C. Glass coverslips used for culturing the cells were first coated with agarose (0.15% wt/vol) and then sprayed with a fine mist of poly-D-lysine (0.1 mg/ml) and rat-tail collagen (0.5 mg/ml) from a glass microatomizer and sterilized by ultraviolet exposure. This produced microislands of permissive substrate with diameters of between 100 and 1000 μm. At 3 or 4 days after plating, when the glial cell layer was approximately 80% confluent, an antimitotic agent (cytosine β-D-arabinofuranoside, 5 μM) was added to arrest glial cell proliferation. Neuronal cultures were then allowed to mature for another 4–9 days. We used microislands that contained single, isolated neurons in which axonal processes and dendritic trees formed multiple self-synapses (autapses). This procedure provided a large population of either excitatory or inhibitory monosynaptic connections.
Back to Top | Article Outline
Electrophysiology
The neurons were voltage clamped using the whole cell recording technique (Axopatch 200 amplifier; Axon Instruments, Foster City, CA). Electrodes were fabricated from borosilicate glass and typically had resistances between 3 and 5 MΩ. Series resistance was compensated by 75–90%. Neurons were voltage clamped at −60 mV, and synaptic responses were stimulated by a 2-ms depolarizing pulse to +20 mV. Shortly after the restoration of the membrane potential to −60 mV, a large (1- to 20-nA) postsynaptic current was observed and recorded. For the synaptic measurements, data were sampled at 50 kHz, filtered at 20 kHz (−3 dB, eight-pole Bessel), and stored on a computer. The extracellular recording solution was 137 mM NaCl, 5 mM KCl, 3 mM CaCl2, 5 mM HEPES, 10 mM glucose, 0.001 mM glycine, and 0.0001 mM strychnine–HCl, titrated to pH 7.3 with NaOH; and the intracellular (pipette) solution was 140 mM KCl, 4 mM NaCl, 0.5 mM EGTA, 2 mM MgATP, and 10 mM HEPES, titrated to pH 7.25 with KOH.
For the experiments in which GABA or glutamate were exogenously applied, the neurons were grown in mass culture and used 3–11 days after plating. Data were sampled at 200 Hz and filtered at 100 Hz (−3 dB, eight-pole Bessel). The extracellular recording solution for glutamate-evoked responses was 150 mM NaCl, 4 mM KCl, 2 mM CaCl2, 10 mM HEPES, 10 mM glucose, 0.0002 mM tetrodotoxin citrate (Tocris Cookson, Bristol, UK), 0.1 mM picrotoxin, 0.0001 mM strychnine–HCl, and 0.001 mM glycine, titrated to pH 7.40 with NaOH; the extracellular recording solution for GABA-evoked responses was 150 mM NaCl, 4 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, and 0.0002 mM tetrodotoxin citrate, titrated to pH 7.40 with NaOH; the intracellular (pipette) solution for GABA- and glutamate-evoked responses was 140 mM CsCl, 3 mM NaCl, 11 mM EGTA, 2 mM MgATP, 10 mM HEPES, titrated to pH 7.20 with CsOH. Unless otherwise stated, all chemicals were obtained from Sigma Chemical (Poole, Dorset, UK). Test solutions were applied to the cells using a rapid-switching perfusion system. 19 All electrophysiologic measurements were carried out at room temperature (20–23°C).
Back to Top | Article Outline
Preparation of Anesthetic Solutions
Isoflurane solutions were prepared as fractions of an aqueous saturated solution at room temperature. The concentration of a saturated solution was taken to be 15.3 mM. 20 Reservoirs containing the anesthetic solutions were sealed with rigid plastic floats, and all tubing and valves were made of polytetrafluoroethylene. With these precautions, losses of anesthetic from the perfusion system were found to be negligible, as measured by gas chromatography. 21 Isoflurane was obtained from Abbott Laboratories (Queenborough, Kent, UK). Solutions for the xenon experiments were prepared by first bubbling pure gases (oxygen, nitrogen, or xenon) through fine sintered-glass bubblers in 250- or 500-ml Drechsel bottles filled with extracellular recording saline. Solutions were bubbled for 1.5–2.0 h, although equilibrium was reached within 45 min. (To minimize oxidation, the neurotoxins and neurotransmitters were absent in the fully oxygenated saline but present at the appropriate concentrations in the xenon and nitrogen solutions.) During bubbling, the solutions were continually stirred at room temperature. These solutions were then mixed to achieve the desired final concentrations of the gases. Control solutions usually contained 80% of the nitrogen solution and 20% of the oxygen solution; test solutions usually contained 80% of the xenon solution and 20% of the oxygen solution. Using a Bunsen water–gas partition coefficient 22 of 0.0965 we calculated that the standard test solution contained 3.4 mM xenon. Xenon (research grade, 99.993% pure) was supplied by BOC Gases (Guildford, Surrey, UK). In all cases, xenon and isoflurane were preapplied to the neurons for at least 30 s before the initiation of synaptic currents.
Back to Top | Article Outline
Integration of the Synaptic Responses
To obtain an estimate for the total charge transfer, the excitatory postsynaptic currents (EPSCs) or inhibitory postsynaptic currents (IPSCs) were integrated numerically. However, because in some cases the currents had not decayed to baseline by the end of the recording period, a correction (which was invariably less than 5% of the total charge transfer) was applied by extrapolating the observed current to the baseline using a biexponential fit to the decay phase of the response (see Results).
Back to Top | Article Outline

Results

Control Synaptic Currents
Fig. 1
Fig. 1
Image Tools
Table 1
Table 1
Image Tools
We first characterized the control synaptic currents, which, consistent with the findings of previous studies, 15,17 almost invariably fell into one of two populations. Approximately half the cells exhibited postsynaptic currents that decayed relatively rapidly (∼8-ms half-time); the other half exhibited currents that were markedly slower (∼40-ms half-time;fig. 1;table 1). The more rapid responses were recorded from cells with a rounded appearance and complex dendritic trees. Their sensitivity to kynurenic acid (80 ± 3% inhibition of the peak current with 1 mM kynurenic acid; n = 7 cells) and insensitivity to bicuculline (0.4 ± 1.3% inhibition of the peak current with 10 μM bicuculline; n = 13 cells) identifies these cells as excitatory glutamatergic neurons. In contrast, the slower synaptic currents were almost completely blocked by bicuculline (94 ± 1% inhibition of the peak current with 10 μM bicuculline; n = 8 cells) and unaffected by kynurenic acid (6 ± 4% inhibition of the peak current with 1 mM kynurenic acid; n = 5 cells), thus identifying these responses as GABAergic. These inhibitory neurons tended to be flatter, with simpler dendritic trees. Because of the recent finding that GABA and glycine can be coreleased by spinal cord interneurons, 23 we considered the possibility that the inhibitory responses we were recording were mediated, in part, by glycine receptors. However, the control current was barely affected (4 ± 2% inhibition; n = 6 cells) by 100 nM strychnine, confirming that the inhibitory currents were entirely GABAergic.
Equation 1
Equation 1
Image Tools
The excitatory and inhibitory currents had essentially identical rise times (table 1), and the peaks of the currents changed linearly with test potential (insets to fig. 1). The decay phase of the synaptic current I(t), in which t is the time measured from the peak of the current, was fit by a biexponential equation of the form MATH 1 where Ifast and Islow are the amplitudes and τfast and τslow are the time constants of the fast and slow components, respectively. The values for these decay–time constants measured from control excitatory and inhibitory responses are given in table 1. In each case, approximately two thirds of the total charge transfer was carried by the slow component. For the excitatory glutamatergic responses, this slow component can be readily identified as mediated by NMDA receptors because it is completely (99 ± 1%; n = 10 cells) blocked by 200 μM DL-2-amino-5-phosphonopentanoate (AP5), a highly selective NMDA receptor antagonist. 24 In the presence of this concentration of AP5, the decay phase of the synaptic current could be fitted well by a single exponential with a magnitude and time course little different from those of the control fast component. This fast component, which very largely determines the magnitude of the peak excitatory current (Ifast/Itotal = 92 ± 1%; n = 13 cells), can be attributed to currents mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors. 15,17
Back to Top | Article Outline
Effects of Isoflurane on Excitatory Currents
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
We next looked at the effects of the inhalational general anesthetic isoflurane on excitatory glutamatergic currents. Isoflurane had a qualitatively similar effect at all concentrations tested. Representative traces are shown in figure 2A. The peak of the synaptic current, and the total charge transfer, decreased monotonically with increasing concentrations of isoflurane (figs. 2B and C). At the highest concentration studied (1.22 mM), the peak was reduced by ∼50% and the total charge transfer by ∼70%. Underlying these gross changes, an analysis of the decay phase of the response revealed subtly different effects of isoflurane on the fast and slow components. For the slow (NMDA receptor) component, the time constant τslow, although rather variable, did not change significantly (fig. 3A). Similarly, the time constant for the fast (AMPA/kainate receptor) component τfast decreased only slightly with increasing concentrations of isoflurane (at 1.22 mM isoflurane, τfast was reduced by ∼25%). The amplitudes of the two components, however, were rather more sensitive to isoflurane, and both decreased by approximately the same percentage (fig. 3B). Overall, the reduction in charge transfer by isoflurane was comparable for the NMDA and AMPA/kainate receptor–mediated components (fig. 3C); this was caused predominantly by reductions in peak amplitude.
To determine the extent to which this inhibition in the EPSC amplitude (fig. 2B) could be accounted for by an effect on the postsynaptic receptors, we measured the inhibition by isoflurane of the current induced by exogenously applied glutamate (100 μM). We found that, at the highest isoflurane concentration used (1.22 mM), the peak of the glutamate-evoked current was reduced by 30 ± 3% (n = 13 cells; inset to fig. 2B).
Table 2
Table 2
Image Tools
Equation 2
Equation 2
Image Tools
To assess the possible importance of these changes to the maintenance of the anesthetic state, it is crucial to quantify the changes in the control synaptic parameters (table 1) at isoflurane concentrations that are of clinical relevance. It has long been recognized that the most appropriate surgical benchmark is the concentration of a general anesthetic that prevents a purposeful response to a painful stimulus in 50% of a population of patients (or animals). For inhalational agents, this concentration is the minimum alveolar concentration (MAC). 25 For inhalational anesthetics, these gas concentrations can be converted to aqueous concentrations using Ostwald or Bunsen water–gas partition coefficients. 26 For isoflurane acting on humans, the MAC in aqueous solution is 270 μM; for the rat it is 310 μM. 14 The percentage changes in the various excitatory synaptic parameters for an isoflurane concentration of ∼1 MAC are given in table 2.
Back to Top | Article Outline
Effects of Isoflurane on Inhibitory Currents
Fig. 4
Fig. 4
Image Tools
Fig. 5
Fig. 5
Image Tools
The effects of isoflurane on inhibitory synaptic currents were qualitatively different from those observed on excitatory currents. Representative traces are shown in figure 4A. Although the peak of the synaptic current was inhibited at high isoflurane concentrations (reaching approximately 40% inhibition at the highest concentration tested, 1.22 mM), the inhibition was very modest over the clinically relevant range (fig. 4B). At each concentration of isoflurane, however, there was a significant increase in the total charge transfer (fig. 4C), which reached an apparent maximum of approximately 130% (i.e., a 2.3-fold increase). An analysis of the kinetics of the decay phase revealed significantly different sensitivities for the fast and slow components. Although the time constants τfast and τslow increased with increasing concentrations of isoflurane (fig. 5A) by roughly the same extent (∼1.8-fold at 1.22 mM), the effects on the amplitudes were qualitatively different, with Islow increasing somewhat and Ifast being strongly inhibited (fig. 5B). The net result is that the total charge carried by the fast component of the inhibitory current decreased modestly, and the charge transferred by the slow component increased markedly (fig. 5C).
The percentage changes in the various inhibitory synaptic parameters at about 1 MAC isoflurane are given in table 2.
Back to Top | Article Outline
Effects of Xenon on Synaptic Currents
Fig. 6
Fig. 6
Image Tools
The gaseous concentration of xenon that prevents a response to a painful stimulus (i.e., MAC) appears to vary among species, being 71% atm in humans, 27 98% atm in rhesus monkeys, 28 and 161% atm in rats. 29 If these values are converted to free aqueous concentrations at 37°C, 14,26 using an Ostwald water–gas partition coefficient of 0.0887, 30 we obtain values of 2.5 mM, 3.4 mM, and 5.6 mM for humans, monkeys, and rats, respectively, with the average value being 3.8 mM. For our experiments, performed at room temperature, the concentration of xenon in the standard test solution was 3.4 mM. At this concentration, xenon had negligible effects on the inhibitory synaptic currents, but strongly depressed the excitatory currents. This is illustrated with representative traces in figure 6.
Table 3
Table 3
Image Tools
For the GABAergic synaptic currents, 3.4 mM xenon affected neither the peak value nor the time course of the postsynaptic currents. Percentage changes in the various inhibitory synaptic parameters are listed in table 3, in which it can be seen that none were significantly changed. We also looked for effects of xenon on currents evoked by a low (3 μM) concentration of exogenously applied GABA. Here, 4.3 mM xenon had no significant effect on the GABA-induced current (2 ± 3% potentiation; n = 4 cells). A representative pair of traces is shown in the inset to figure 6A. In contrast, 3.4 mM xenon greatly depressed the glutamatergic synaptic current, with the effect being confined, almost exclusively, to the slow NMDA receptor–mediated component of the current (fig. 6B). This is evident in the percentage changes in the various excitatory synaptic parameters, which are listed in table 3. Here it can be seen that the qualitative effects of xenon are remarkably closely mimicked by the effects of AP5. At the concentration of AP5 used (200 μM), the NMDA receptor component would be expected to be almost completely blocked 24,31; this is consistent with the 99% block of Islow (table 3). This is accompanied by a 75% reduction in total charge transfer, close to the 61% of the total charge that we estimate to be carried by the slow NMDA receptor–mediated component (table 1). The difference may be accounted for by the small but significant reduction of the fast time constant τfast by AP5 (table 3). Likewise, xenon causes a large inhibition (70%) of Islow and a large inhibition (56%) of the total charge transfer, with only a small effect on the fast AMPA/kainate receptor–mediated component.
Back to Top | Article Outline

Discussion

Effects of Isoflurane on Excitatory Currents
Isoflurane, at clinically relevant concentrations, modestly but significantly depressed glutamatergic EPSCs (fig. 2;table 2). This finding is qualitatively consistent with previous observations of postsynaptic potentials in brain slice preparations, 9,10,32 and with some studies using other volatile agents. 11,33,34
The principal effects we observed were a concentration-dependent reduction in the amplitude of the EPSC and, concomitantly, a reduction in the total charge transfer (fig. 2). The overall time course of the EPSC was affected less. Similarly, when the decay phase of the postsynaptic current was analyzed, the main effects were a reduction in the amplitudes of the fast and slow components, with their respective time constants being only slightly reduced (fig. 3); fast and slow components of charge transfer were affected equally. Hence the two major subclasses of glutamate receptor (NMDA and AMPA/kainate) mediate currents that are roughly equally sensitive to isoflurane.
The sensitivity to isoflurane of responses to exogenously applied glutamate (inset to fig. 2B) suggests that approximately half of the effect of isoflurane on the peak of the EPSC can be accounted for by an inhibition of postsynaptic receptors. Unfortunately, there are very few studies on the effects of volatile anesthetics on postsynaptic glutamate receptors. Because of the very fast decay kinetics of glutamate-activated currents, 35 results using either slow perfusion in brain slice preparations 11 or incubation with glutamate in binding experiments 36 are very difficult to extrapolate to functional synapses. However, in our experiments, the rate of agonist application was not ultrarapid, as is necessary to accurately measure peak responses. We were also limited to studying extrajunctional receptors in which subunit composition and pharmacology might differ from synaptic receptors. 37 Even so, from our results and the best available data, 38–40 it seems likely that much of the effect of isoflurane at glutamatergic synapses is postsynaptic in origin. Future work on miniature EPSCs may help to clarify this point.
This leaves a significant component of the inhibition of the EPSC, however, that must presumably be presynaptic. 10 The presynaptic targets may be voltage-gated calcium channels, although this is difficult to assess. The predominant calcium channel that mediates neurotransmitter release at hippocampal glutamatergic synapses, the P/Q-type channel, 41,42 is very insensitive to isoflurane. 43,44 Conversely, neurotransmitter release can be sensitive to small changes in presynaptic calcium entry 45; therefore, a small inhibition of calcium channels might translate into larger changes in glutamate release.
Back to Top | Article Outline
Effects of Isoflurane on Inhibitory Currents
The effects of isoflurane on GABAergic IPSCs were, for the most part, qualitatively and quantitatively different from its effects on glutamatergic EPSCs. The one feature in common (figs. 2B and 4B) was a concentration-dependent decrease in the amplitude of the postsynaptic current, although there was no significant inhibition of the IPSC amplitude over the clinically relevant range of concentrations. The predominant effect of isoflurane was a marked prolongation in the time course of the IPSC, which, even with the reduction in the peak amplitude at higher concentrations, always translated into a substantial increase in the total charge transfer (fig. 4C). These findings are consistent with some previous voltage-clamp studies of volatile anesthetics acting at GABAergic synapses. 5,12,46
An analysis of the kinetics of the IPSC showed that, although both time constants (τfast and τslow) increased monotonically with increasing anesthetic concentration (fig. 5A), the amplitude of the slow component increased slightly but the amplitude of the fast component was strongly inhibited (fig. 5B). These combined effects resulted in a large increase in the charge transferred by the slow component of the IPSC, with little effect—in fact, a small reduction—in the charge carried by the fast component (fig. 5C). Similar results with volatile anesthetics have been reported by Jones and Harrison 12 with cultured hippocampal neurons, and by Pearce 46 with hippocampal slices.
The finding that isoflurane effectively only changes the charge transfer through the slow component of the IPSC poses an important question: Does this slow component reflect the existence of a population of GABAA receptors that is particularly sensitive to anesthetics, or does it simply reflect the complexity of channel kinetics? It has been suggested that kinetically distinct GABAA receptors may underlie the two components of GABAergic IPSCs, 47 and that these different receptor subtypes have very different anesthetic sensitivities. 46,48 However, this has yet to be shown in expression systems in vitro. 49 Moreover, it has been shown that a homogeneous population of GABAA receptors can display biexponential decay kinetics, 50 indicating that the two decay components can simply result from different conducting states of a single GABAA receptor subtype. 51,52 Therefore, isoflurane could act by stabilizing one or more of the longer lived open states, or by affecting the kinetics of transitions between different states. Until more is known about the factors responsible for the biphasic decay of GABAergic IPSCs, however, this question remains difficult to answer.
In regard to the molecular site of action at inhibitory synapses, there can be little doubt that isoflurane exerts its principal effects postsynaptically; but, as with glutamatergic synapses, there may be small effects presynaptically that could be responsible for some of the depression in the amplitude of the IPSC (fig. 4B) at higher isoflurane concentrations. However, a thorough study of the effects of isoflurane on miniature IPSCs in hippocampal neurons 48 strongly suggests that much of this depression can be attributed to direct actions on the postsynaptic receptors.
Back to Top | Article Outline
Effects of Xenon on Synaptic Currents
The selectivity of action found with xenon was unexpected. 13 Because almost all general anesthetics potentiate the actions of GABA at GABAA receptors, 53,54 we anticipated that xenon would be no exception. However, the complete absence of an effect of xenon on GABAA receptors puts it into the same class of agents as ketamine, a so-called dissociative anesthetic, which is also ineffective at GABAA receptors 55 and is thought to act predominantly at NMDA receptors. Similarly, our results show that xenon selectively blocks NMDA receptors with little effect at AMPA/kainate receptors. This latter result strongly suggests that the actions of xenon are postsynaptic in origin. The lack of an effect of xenon on the decay time of the NMDA receptor component, however, rules out a simple open-channel block mechanism of inhibition, as do data 13 showing that xenon noncompetitively inhibits NMDA-evoked currents without affecting the NMDA EC50 (half-maximal) concentration. Whatever the exact molecular basis for the surprising selectivity of xenon for NMDA receptors, this selectivity simply accounts for many features of the unusual pharmacologic profile of xenon. NMDA receptor antagonists share a number of common features, including the ability to induce profound analgesia and psychotomimetic effects. A strong case has been made 56 that nitrous oxide (laughing gas) exerts many of its effects in this way. Likewise, we suggest that the action of xenon at NMDA receptors accounts for many of its analgesic and anesthetic properties, and its ability to induce a state of euphoria. 57 Consistent with this, the much smaller inhibition of the NMDA receptor by isoflurane correlates with its relative lack of analgesic potency. 58
Back to Top | Article Outline
Significance for Anesthetic Mechanisms
We determined that isoflurane and xenon are surprisingly selective in their actions, having very different effects on excitatory and inhibitory synaptic transmission. At clinically relevant concentrations, isoflurane has its greatest effect at GABAergic synapses, causing a marked potentiation of total charge transfer. At glutamatergic synapses, the effects of isoflurane are smaller, but still significant. Although both of these effects may contribute to the anesthetic actions of isoflurane, additional criteria (e.g., stereoselectivity) are needed before the relative importance of these effects can be assessed. 59 Moreover, the relation between anesthetic-induced changes in charge transfer at individual synapses and changes in the firing patterns of neuronal networks involved in anesthesia are unknown. The actions of xenon may be accounted for solely in terms of effects at glutamatergic synapses, although other targets may well be identified in the future. Nonetheless, the insensitivity of GABAergic synapses to xenon indicates that its mechanisms of action are clearly different from those of most general anesthetics. At the mechanistic level, it is clear that, for both xenon and isoflurane, postsynaptic receptors are the most important molecular targets.
The authors thank Professor R. M. Jones for the gift of xenon, and Drs. L. M. Franks and J. M. Bekkers for help with nerve culturing.
Back to Top | Article Outline

References

1. Larrabee MG, Posternak JM: Selective action of anesthetics on synapses and axons in mammalian sympathetic ganglia. J Neurophysiol 1952; 15:91–114

2. Pocock G, Richards CD: Excitatory and inhibitory synaptic mechanisms in anaesthesia. Br J Anaesth 1993; 71:134–47

3. MacIver MB, Roth SH: Inhalational anaesthetics exhibit pathway-specific and differential actions on hippocampal synaptic responses in vitro. Br J Anaesth 1988; 60:680–91

4. Pearce RA, Stringer JL, Lothman ER: Effect of volatile anesthetics on synaptic transmission in the rat hippocampus. A NESTHESIOLOGY 1989; 71:591–8

5. Gage PW, Robertson B: Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus. Br J Pharmacol 1985; 85:675–81

6. Mody I, Tanelian DL, MacIver MB: Halothane enhances tonic neuronal inhibition by elevating intracellular calcium. Brain Res 1991; 538:319–23

7. Fujiwara N, Higashi H, Nishi S, Shimoji K, Sugita S, Yoshimura M: Changes in spontaneous firing patterns of rat hippocampal neurones induced by volatile anaesthetics. J Physiol 1988; 402:155–75

8. Yoshimura M, Higashi H, Fujita S, Shimoji K: Selective depression of hippocampal inhibitory postsynaptic potentials and spontaneous firing by volatile anesthetics. Brain Res 1985; 340:363–8

9. Miu P, Puil E: Isoflurane-induced impairment of synaptic transmission in hippocampal neurons. Exp Brain Res 1989; 75:354–60

10. MacIver MB, Mikulec AA, Amagasu SM, Monroe FA: Volatile anesthetics depress glutamate transmission via presynaptic actions. A NESTHESIOLOGY 1996; 85:823–34

11. Perouansky M, Baranov D, Salman M, Yaari Y: Effects of halothane on glutamate receptor-mediated excitatory postsynaptic currents. A NESTHESIOLOGY 1995; 83:109–19

12. Jones MV, Harrison NL: Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurophysiol 1993; 70:1339–49

13. Franks NP, Dickinson R, de Sousa SLM, Hall AC, Lieb WR: How does xenon produce anaesthesia? Nature 1998; 396:324

14. Franks NP, Lieb WR: Temperature dependence of the potency of volatile general anesthetics: Implications for in vitro experiments. A NESTHESIOLOGY 1996; 84:716–20

15. Bekkers JM, Stevens CF: Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture. Proc Natl Acad Sci U S A 1991; 88:7834–8

16. Segal MM, Furshpan EJ: Epileptiform activity in microcultures containing small numbers of hippocampal neurons. J Neurophysiol 1990; 64:1390–9

17. Mennerick S, Que J, Benz A, Zorumski CF: Passive and synaptic properties of hippocampal neurons grown in microcultures and in mass cultures. J Neurophysiol 1995; 73:320–32

18. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF: Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 1998; 18:9716–26

19. Downie DL, Hall AC, Lieb WR, Franks NP: Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes. Br J Pharmacol 1996; 118:493–502

20. Franks NP, Lieb WR: Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science 1991; 254:427–30

21. Hall AC, Lieb WR, Franks NP: Stereoselective and non-stereoselective actions of isoflurane on the GABAA receptor. Br J Pharmacol 1994; 112:906–10

22. Smith RA, Porter EG, Miller KW: The solubility of anesthetic gases in lipid bilayers. Biochim Biophys Acta 1981; 645:327–38

23. Jonas P, Bischofberger J, Sandkühler J: Corelease of two fast neurotransmitters at a central synapse. Science 1998; 281:419–24

24. Davies J, Francis AA, Jones AW, Watkins JC: 2-amino-5-phosphonvalerate (2APV), a potent and selective antagonist of amino acid-induced and synaptic excitation. Neurosci Lett 1981; 21:77–81

25. Quasha AL, Eger EI II, Tinker JH: Determination and applications of MAC. A NESTHESIOLOGY 1980; 53:315–34

26. Franks NP, Lieb WR: Selective actions of volatile general anaesthetics at molecular and cellular levels. Br J Anaesth 1993; 71:65–76

27. Cullen SC, Eger EI II, Cullen BF, Gregory P: Observations on the anesthetic effect of the combination of xenon and halothane. A NESTHESIOLOGY 1969; 31:305–9

28. Whitehurst SL, Nemoto EM, Yao L, Yonas H: MAC of xenon and halothane in rhesus monkeys. J Neurosurg Anesthesiol 1994; 6:275–9

29. Koblin DD, Fang Z, Eger EI, II, Laster MJ, Gong D, Ionescu P, Halsey MJ, Trudell JR: Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: Helium and neon as nonimmobilizers. Anesth Analg 1998; 87:419–24

30. Weathersby PK, Homer LD: Solubility of inert gases in biological fluids and tissues: A review. Undersea Biomed Res 1980; 7:277–96

31. Benveniste M, Mayer ML: Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Biophys J 1991; 59:560–73

32. El-Beheiry H, Puil E: Anaesthetic depression of excitatory synaptic transmission in neocortex. Exp Brain Res 1989; 77:87–93

33. Richards CD, White AE: The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus. J Physiol 1975; 252:241–57

34. Richards CD, Smaje JC: Anaesthetics depress the sensitivity of cortical neurones to L-glutamate. Br J Pharmacol 1976; 58:347–57

35. Colquhoun D, Jonas P, Sakmann B: Action of brief pulses of glutamate on AMPA/Kainate receptors in patches from different neurones of rat hippocampal slices. J Physiol 1992; 458:261–87

36. Martin DC, Plagenhoef M, Abraham J, Dennison RL, Aronstam RS: Volatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors. Biochem Pharmacol 1995; 49:809–17

37. Tovar KR, Westbrook GL: The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 1999; 19:4180–8

38. Yang J, Zorumski CF: Effects of isoflurane on N-methyl-D-aspartate gated ion channels in cultured rat hippocampal neurons. Ann NY Acad Sci 1991; 625:287–9

39. Wakamori M, Ikemoto Y, Akaike N: Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat. J Neurophysiol 1991; 66:2014–21

40. Minami K, Wick MJ, Stern-Bach Y, Dildy-Mayfield JE, Brozowski SJ, Gonzales EL, Trudell JR, Harris RA: Sites of volatile anesthetic action on kainate (glutamate receptor 6) receptors. J Biol Chem 1998; 273:8248–55

41. Takahashi T, Momiyama A: Different types of calcium channels mediate central synaptic transmission. Nature 1993; 366:156–8

42. Reid CA, Clements JD, Bekkers JM: Nonuniform distribution of Ca2+ channel subtypes on presynaptic terminals of excitatory synapses in hippocampal cultures. J Neurosci 1997; 17:2738–45

43. Hall AC, Lieb WR, Franks NP: Insensitivity of P-type calcium channels to inhalational and intravenous general anesthetics. A NESTHESIOLOGY 1994; 81:117–23

44. Kameyama K, Aono K, Kitamura K: Isoflurane inhibits neuronal Ca2+ channels through enhancement of current inactivation. Br J Anaesth 1999; 82:402–11

45. Reid CA, Bekkers JM, Clements JD: N- and P/Q-type Ca2+ channels mediate transmitter release with a similar cooperativity at rat hippocampal autapses. J Neurosci 1998; 18:2849–55

46. Pearce RA: Volatile anaesthetic enhancement of paired-pulse depression investigated in the rat hippocampus in vitro. J Physiol 1996; 492 (3):823–40

47. Pearce RA: Physiological evidence for two distinct GABAA responses in rat hippocampus. Neuron 1993; 10:189–200

48. Banks MI, Pearce RA: Dual actions of volatile anesthetics on GABAA IPSCs. Dissociation of blocking and prolonging effects. A NESTHESIOLOGY 1999; 90:120–34

49. Harris RA, Mihic SJ, Dildy-Mayfield JE, Machu TK: Actions of anesthetics on ligand-gated ion channels: Role of receptor subunit composition. FASEB J 1995; 9:1454–62

50. Verdoorn TA, Draguhn A, Ymer S, Seeburg PH, Sakmann B: Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron 1990; 4:919–28

51. Macdonald RL, Rogers CJ, Twyman RE: Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture. J Physiol 1989; 417:483–500

52. Jones MV, Westbrook GL: Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 1995; 15:181–91

53. Tanelian DL, Kosek P, Mody I, MacIver MB: The role of the GABAA receptor/chloride channel complex in anesthesia. A NESTHESIOLOGY 1993; 78:757–76

54. Franks NP, Lieb WR: Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367:607–14

55. Brockmeyer DM, Kendig JJ: Selective effects of ketamine on amino acid-mediated pathways in neonatal rat spinal cord. Br J Anaesth 1995; 74:79–84

56. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW: Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 1998; 4:460–3

57. Kawaguchi T, Mashimo T, Yagi M, Takeyama E, Yoshiya I: Xenon is another laughing gas. Can J Anaesth 1996; 43 (6):641–2

58. Petersen-Felix S, Arendt-Nielsen L, Bak P, Roth D, Fischer M, Bjerring P, Zbinden AM: Analgesic effect in humans of subanaesthetic isoflurane concentrations evaluated by experimentally induced pain. Br J Anaesth 1995; 75:55–60

59. Franks NP, Lieb WR: Which molecular targets are most relevant to general anaesthesia? Toxicol Lett 1998; 100–101:1–8

Cited By:

This article has been cited 110 time(s).

Behavioural Brain Research
A schizophrenia rat model induced by early postnatal phencyclidine treatment and characterized by Magnetic Resonance Imaging
Broberg, BV; Madsen, KH; Plath, N; Olsen, CK; Glenthoj, BY; Paulson, OB; Bjelke, B; Sogaard, LV
Behavioural Brain Research, 250(): 1-8.
10.1016/j.bbr.2013.04.026
CrossRef
Plos One
Auditory Evoked Bursts in Mouse Visual Cortex during Isoflurane Anesthesia
Land, R; Engler, G; Kral, A; Engel, AK
Plos One, 7(): -.
ARTN e49855
CrossRef
Anesthesia and Analgesia
The analgesic effect of xenon on the formalin test in rats: A comparison with nitrous oxide
Fukuda, T; Nishimoto, C; Hisano, S; Miyabe, M; Toyooka, H
Anesthesia and Analgesia, 95(5): 1300-1304.
10.1213/01.ANE.0000030327.48223.11
CrossRef
Naunyn-Schmiedebergs Archives of Pharmacology
Comparison of the effects of xenon and halothane on voltage-dependent Ca2+ fluxes in rabbit T-tubule membranes
Oz, M; Dinc, M; Tchugunova, Y; Dunn, SMJ
Naunyn-Schmiedebergs Archives of Pharmacology, 365(5): 413-417.
10.1007/s00210-002-0541-2
CrossRef
British Journal of Anaesthesia
In vivo genetics of anaesthetic action
Nash, HA
British Journal of Anaesthesia, 89(1): 143-155.

Hearing Research
Argon protects hypoxia-, cisplatin- and gentamycin-exposed hair cells in the newborn rat's organ of Corti
Yarin, YM; Amarjargal, N; Fuchs, J; Haupt, H; Mazurek, B; Morozova, SV; Gross, J
Hearing Research, 201(): 1-9.

Molecular Pain
Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons
Georgiev, SK; Furue, H; Baba, H; Kohno, T
Molecular Pain, 6(): -.
ARTN 25
CrossRef
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Xenon and other volatile anesthetic agents-mode of action
Hecker, K; Rossaint, R
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 36(): 644-646.

Molecular and Basic Mechanisms of Anesthesia
Characterisation of anesthetic. Target sites by fluorescence: Acridine and methyl salicylate have anesthetic properties and interact with albumin and octanol
Jetzek-Zader, M; Lipfert, P
Molecular and Basic Mechanisms of Anesthesia, (): 61-65.

Proceedings of the National Academy of Sciences of the United States of America
Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans
Nagele, P; Metz, LB; Crowder, CM
Proceedings of the National Academy of Sciences of the United States of America, 101(): 8791-8796.

Journal of Pharmacology and Experimental Therapeutics
The N-methyl-D-aspartate receptor inhibitory potencies of aromatic inhaled drugs of abuse: Evidence for modulation by cation-pi interactions
Raines, DE; Gioia, F; Claycomb, RJ; Stevens, RJ
Journal of Pharmacology and Experimental Therapeutics, 311(1): 14-21.
10.1124/jpet.104.069930
CrossRef
Psychopharmacology
Mapping the central effects of ketamine in the rat using pharmacological MRI
Littlewood, CL; Jones, N; O'Neill, MJ; Mitchell, SN; Tricklebank, M; Williams, SCR
Psychopharmacology, 186(1): 64-81.
10.1007/s00213-006-0344-0
CrossRef
Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity: Cocaine, Ghb, and Substituted Amphetamines
Morphological evidence that xenon neuroprotects against N-methyl-DL-aspartic acid-induced damage in the rat arcuate nucleus - A time-dependent study
Natale, G; Cattano, D; Abramo, A; Forfori, F; Fulceri, F; Fornai, F; Paparelli, A; Giunta, F
Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity: Cocaine, Ghb, and Substituted Amphetamines, 1074(): 650-658.
10.1196/annals.1369.063
CrossRef
Nature Reviews Neuroscience
General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal
Franks, NP
Nature Reviews Neuroscience, 9(5): 370-386.
10.1038/nrn2372
CrossRef
British Journal of Anaesthesia
Sodium channels and the synaptic mechanisms of inhaled anaesthetics
Hemmings, HC
British Journal of Anaesthesia, 103(1): 61-69.
10.1093/bja/aep144
CrossRef
Anesthesia and Analgesia
Minimum anesthetic concentration of sevoflurane with different xenon concentrations in swine
Hecker, KE; Baumert, JH; Horn, N; Reyle-Hahn, M; Heussen, N; Rossaint, R
Anesthesia and Analgesia, 97(5): 1364-1369.
10.1213/01.ANE.0000081062.20894.D1
CrossRef
Experimental Biology and Medicine
Endothelin-A receptor blockade does not debilitate the cardiovascular and hormonal adaptation to xenon or isoflurane Anesthesia in dogs
Francis, RCE; Hohne, C; Klein, A; Donaubauer, B; Kaisers, U; Boemke, W
Experimental Biology and Medicine, 231(6): 834-839.

European Journal of Pharmacology
The xenon-mediated antagonism against the NMDA receptor is non-selective for receptors containing either NR2A or NR2B subunits in the mouse amygdala
Haseneder, R; Kratzer, S; Kochs, E; Hofelmann, D; Auberson, Y; Eder, M; Rammes, G
European Journal of Pharmacology, 619(): 33-37.
10.1016/j.ejphar.2009.08.011
CrossRef
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Perspectives for anesthesia with Xenon
Reyle-Hahn, M; Rossaint, R
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 36(6): 377-380.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Is there a future for xenon anesthesia?
Goto, T
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 49(4): 335-338.

Progress in Nuclear Magnetic Resonance Spectroscopy
Hyperpolarised xenon in biology
Cherubini, A; Bifone, A
Progress in Nuclear Magnetic Resonance Spectroscopy, 42(): 1-30.
PII S0079-6565(02)00052-3
CrossRef
Perfusion-Uk
Microbubble production in an in vitro cardiopulmonary bypass circuit ventilated with Xenon
Casey, ND; Chandler, J; Gifford, D; Falter, F
Perfusion-Uk, 20(3): 145-150.
10.1191/0267659105pf799oa
CrossRef
Anesthesia and Analgesia
Actions of norepinephrine and isoflurane on inhibitory synaptic transmission in adult rat spinal cord substantia gelatinosa neurons
Georgiev, SK; Wakai, A; Kohno, T; Yamakura, T; Baba, H
Anesthesia and Analgesia, 102(1): 124-128.
10.1213/01.ane.0000184829.25310
CrossRef
Experimental Brain Research
Contributions of GABAergic and glutamatergic mechanisms to isoflurane-induced suppression of thalamic somatosensory information transfer
Vahle-Hinz, C; Detsch, O; Siemers, M; Kochs, E
Experimental Brain Research, 176(1): 159-172.
10.1007/s00221-006-0604-6
CrossRef
Annual Review of Pharmacology and Toxicology
Anesthetics and ion channels: Molecular models and sites of action
Yamakura, T; Bertaccini, E; Trudell, JR; Harris, RA
Annual Review of Pharmacology and Toxicology, 41(): 23-51.

Naturwissenschaften
How do general anaesthetics work?
Antkowiak, B
Naturwissenschaften, 88(5): 201-213.

British Journal of Anaesthesia
In vitro networks: subcortical mechanisms of anaesthetic action
Kendig, JJ
British Journal of Anaesthesia, 89(1): 91-101.

Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
Cerebral effects of volatile anaesthetics - What do we really know?
Antkowiak, B
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 36(6): 365-367.

Anesthesia and Analgesia
Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration
Sonner, JM; Antognini, JF; Dutton, RC; Flood, P; Gray, AT; Harris, RA; Homanics, GE; Kendig, J; Orser, B; Raines, DE; Trudell, J; Vissel, B; Eger, EI
Anesthesia and Analgesia, 97(3): 718-740.
10.1213/01.ANE.0000081063.76651.33
CrossRef
Journal of Biological Chemistry
Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics
Fang, M; Tao, YX; He, FH; Zhang, MJ; Levine, CF; Mao, PZ; Tao, F; Chou, CL; Sadegh-Nasseri, S; Johns, RA
Journal of Biological Chemistry, 278(): 36669-36675.
10.1074/jbc.M303520200
CrossRef
British Journal of Pharmacology
Pentobarbitone modulates calcium transients in axons and synaptic boutons of hippocampal CA1 neurons
Baudoux, S; Empson, RM; Richards, CD
British Journal of Pharmacology, 140(5): 971-979.
10.1038/sj.bjp.0705519
CrossRef
Anesthesia and Analgesia
Halothane and propofol modulation of gamma-aminobutyric acid(A) receptor single-channel currents
Kitamura, A; Sato, R; Marszalec, W; Yeh, JZ; Ogawa, R; Narahashi, T
Anesthesia and Analgesia, 99(2): 409-415.

Anesthesia and Analgesia
Isoflurane depresses windup of C fiber-evoked limb withdrawal with variable effects on nociceptive lumbar spinal neurons in rats
Jinks, SL; Antognini, JF; Dutton, RC; Carstens, E; Eger, EI
Anesthesia and Analgesia, 99(5): 1413-1419.
10.1213/01.ANE.0000135635.32227.DA
CrossRef
Anesthesia and Analgesia
Anesthetic sensitivities to propofol and halothane in mice lacking the R-Type (Ca(v)2.3) Ca2+ channel
Takei, T; Saegusa, H; Zong, SQ; Murakoshi, T; Makita, K; Tanabe, T
Anesthesia and Analgesia, 97(1): 96-103.
10.1213/01.ANE.0000065548.83253.5C
CrossRef
Anasthesiologie & Intensivmedizin
How do anaesthetics act?
Tonner, PH
Anasthesiologie & Intensivmedizin, 47(): 265-+.

Neuroimage
Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat
Littlewood, CL; Cash, D; Dixon, AL; Dix, SL; White, CT; O'Neill, MJ; Tricklebank, M; Williams, SCR
Neuroimage, 32(4): 1733-1746.
10.1016/j.neuroimage.2006.05.022
CrossRef
Anesthesia and Analgesia
Riluzole, a glutamate release inhibitor, induces loss of righting reflex, antinociception, and immobility in response to noxious stimulation in mice
Irifune, M; Kikuchi, N; Saida, T; Takarada, T; Shimizu, Y; Endo, C; Morita, K; Dohi, T; Sato, T; Kawahara, M
Anesthesia and Analgesia, 104(6): 1415-1421.
10.1213/01.ane.0000263267.04198.36
CrossRef
Journal of Neurophysiology
Evidence that Xenon does not produce open channel blockade of the NMDA receptor
Weigt, HU; Adolph, O; Georgieff, M; Georgieff, EM; Fohr, KJ
Journal of Neurophysiology, 99(4): 1983-1987.
10.1152/jn.00631.2007
CrossRef
Anesthesia and Analgesia
Nitrous oxide and xenon increase the efficacy of GABA at recombinant mammalian GABA(A) receptors
Hapfelmeier, G; Zieglgansberger, W; Haseneder, R; Schneck, H; Kochs, E
Anesthesia and Analgesia, 91(6): 1542-1549.

Bmc Neuroscience
Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices
Pittson, S; Himmel, AM; MacIver, MB
Bmc Neuroscience, 5(): -.
ARTN 52
CrossRef
Acta Neurobiologiae Experimentalis
Xenon blocks AMPA and NMDA receptor channels by different mechanisms
Weigt, HU; Fohr, KJ; Georgieff, M; Georgieff, EM; Senftleben, U; Adolph, O
Acta Neurobiologiae Experimentalis, 69(4): 429-440.

British Journal of Anaesthesia
The effects of general anaesthetics on ligand-gated ion channels
Dilger, JP
British Journal of Anaesthesia, 89(1): 41-51.

British Journal of Anaesthesia
Anaesthetic modulation of synaptic transmission in the mammalian CNS
Richards, CD
British Journal of Anaesthesia, 89(1): 79-90.

Brain Research
Effects of isoflurane on auditory middle latency (MLRs) and steady-state (SSRs) responses recorded from the temporal cortex of the rat
Santarelli, R; Carraro, L; Conti, G; Capello, M; Plourde, G; Arslan, E
Brain Research, 973(2): 240-251.
10.1016/S0006-8993(03)02520-4
CrossRef
Neuroimage
Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness
White, NS; Alkire, MT
Neuroimage, 19(2): 402-411.
10.1016/S1053-8119(03)00103-4
CrossRef
Journal of Pharmacology and Experimental Therapeutics
Effects of halothane and propofol on excitatory and inhibitory synaptic transmission in rat cortical neurons
Kitamura, A; Marszalec, W; Yeh, JZ; Narahashi, T
Journal of Pharmacology and Experimental Therapeutics, 304(1): 162-171.
10.1124/jpet.102.043273
CrossRef
Anesthesia and Analgesia
Xenon does not affect gamma-aminobutyric acid type a receptor binding in humans
Salmi, E; Laitio, RM; Aalto, S; Maksimow, AT; Langsjo, JW; Kaisti, KK; Aantaa, R; Oikonen, V; Metsahonkala, L; Nagren, K; Korpi, ER; Scheinin, H
Anesthesia and Analgesia, 106(1): 129-134.
10.1213/01.ane.0000287658.14763.13
CrossRef
Anesthesia and Analgesia
Enflurane decreases glutamate neurotransmission to spinal cord motor neurons by both pre- and postsynaptic actions
Cheng, G; Kendig, JJ
Anesthesia and Analgesia, 96(5): 1354-1359.
10.1213/01.ANE.0000055649.06649.D2
CrossRef
Neuropharmacology
The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro
Dickinson, R; Awaiz, S; Whittington, MA; Lieb, WR; Franks, NP
Neuropharmacology, 44(7): 864-872.
10.1016/S0028-3908(03)00083-2
CrossRef
Journal of Neuroscience Methods
On the use of isoflurane versus halothane in the study of visual response properties of single cells in the primary visual cortex
Villeneuve, MY; Casanova, C
Journal of Neuroscience Methods, 129(1): 19-31.
10.1016/S0165-0270(03)00198-5
CrossRef
European Journal of Pharmacology
Xenon suppresses nociceptive reflex in newborn rat spinal cord in vitro; comparison with nitrous oxide
Watanabe, I; Takenoshita, M; Sawada, T; Uchida, I; Mashimo, T
European Journal of Pharmacology, 496(): 71-76.
10.1016/j.ejphar.2004.06.005
CrossRef
Physical Review E
Modeling the effects of anesthesia on the electroencephalogram
Bojak, I; Liley, DTJ
Physical Review E, 71(4): -.
ARTN 041902
CrossRef
British Medical Bulletin
Xenon: elemental anaesthesia in clinical practice
Sanders, RD; Ma, DQ; Maze, M
British Medical Bulletin, 71(1): 115-135.
10.1093/bmb/ldh034
CrossRef
Acta Neurobiologiae Experimentalis
In vitro-evaluation of lipid emulsions as vehicles for the administration of xenon: Interaction with NMDA receptors
Weigt, HU; Georgieff, M; Fohr, KJ; Adolph, O
Acta Neurobiologiae Experimentalis, 69(2): 207-216.

Anesthesia and Analgesia
Local GABA(A) receptor blockade reverses isoflurane's suppressive effects on thalamic neurons in vivo
Vahle-Hinz, C; Detsch, O; Siemers, M; Kochs, E; Bromm, B
Anesthesia and Analgesia, 92(6): 1578-1584.

Brain Research
Differential modulation of GABA- and NMDA-gated currents by ethanol and isoflurane in cultured rat cerebral cortical neurons
Ming, Z; Knapp, DJ; Mueller, RA; Breese, GR; Criswell, HE
Brain Research, 920(): 117-124.

British Journal of Anaesthesia
Differential effects of isoflurane on excitatory and inhibitory synaptic inputs to thalamic neurones in vivo
Detsch, O; Kochs, E; Siemers, M; Bromm, B; Vahle-Hinz, C
British Journal of Anaesthesia, 89(2): 294-300.

British Journal of Anaesthesia
Xenon: no stranger to anaesthesia
Sanders, RD; Franks, NP; Maze, M
British Journal of Anaesthesia, 91(5): 709-717.
10.1093/bja/aeg232
CrossRef
British Journal of Anaesthesia
Entropy is blind to nitrous oxide. Can we see why?
Sleigh, JW; Barnard, JPM
British Journal of Anaesthesia, 92(2): 159-161.
10.1093/bja/aeh039
CrossRef
Anesthesia and Analgesia
Volatile aromatic Anesthetics variably impact human gamma-aminobutyric acid type a receptor function
Kelly, EW; Solt, K; Raines, DE
Anesthesia and Analgesia, 105(5): 1287-1292.
10.1213/01.ane.0000282829.21797.97
CrossRef
Laboratory Animals
The haemodynamic and catecholamine response to xenon/remifentanil anaesthesia in Beagle dogs
Francis, RCE; Reyle-Hahn, MS; Hohne, C; Klein, A; Theruvath, I; Donaubauer, B; Busch, T; Boemke, W
Laboratory Animals, 42(3): 338-349.
10.1258/la.2007.007048
CrossRef
Anesthesia and Analgesia
A Comparison of the Molecular Bases for N-Methyl-D-Aspartate-Receptor Inhibition Versus Immobilizing Activities of Volatile Aromatic Anesthetics
Sewell, JC; Raines, DE; Eger, EI; Laster, MJ; Sear, JW
Anesthesia and Analgesia, 108(1): 168-175.
10.1213/ane.0b013e31818de158
CrossRef
Acta Oto-Laryngologica
Effects of isoflurane on the auditory brainstem responses and middle latency responses of rats
Santarelli, R; Arslan, E; Carraro, L; Conti, G; Capello, M; Plourde, G
Acta Oto-Laryngologica, 123(2): 176-181.
10.1080/0036554021000028108
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility
Irifune, M; Katayama, S; Takarada, T; Shimizu, Y; Endo, C; Takata, T; Morita, K; Dohi, T; Sato, T; Kawahara, M
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 54(): 998-1005.

Biochemistry
Predictability of weak binding from X-ray crystallography: Inhaled anesthetics and myoglobin
Tanner, JW; Johansson, JS; Liebman, PA; Eckenhoff, RG
Biochemistry, 40(): 5075-5080.

Molecular Pharmacology
The general anesthetic Isoflurane depresses synaptic vesicle exocytosis
Hemmings, HC; Yan, W; Westphalen, RI; Ryan, TA
Molecular Pharmacology, 67(5): 1591-1599.
10.1124/mol.104.003210
CrossRef
British Journal of Anaesthesia
Isoflurane exerts antinociceptive and hypnotic properties at all ages in Fischer rats
Sanders, RD; Patel, N; Hossain, M; Ma, D; Maze, M
British Journal of Anaesthesia, 95(3): 393-399.
10.1093/bja/aei182
CrossRef
British Journal of Anaesthesia
Xenon neuroprotection against hypoxia-ischaemia is mediated by the N-methyl-D-aspartate receptor glycine site
Banks, P; Franks, NP; Dickinson, R
British Journal of Anaesthesia, 104(4): 526.

Anesthesiology
Ion channels take center stage - Twin spotlights on two anesthetic targets
Harrison, NL
Anesthesiology, 92(4): 936-938.

Molecular and Basic Mechanisms of Anesthesia
Anesthetic actions on the spinal cord in vitro
Kendig, J
Molecular and Basic Mechanisms of Anesthesia, (): 376-380.

Molecular Pharmacology
Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane
Gruss, M; Bushell, TJ; Bright, DP; Lieb, WR; Mathie, A; Franks, NP
Molecular Pharmacology, 65(2): 443-452.

Biochimica Et Biophysica Acta-Molecular Cell Research
Alcohols increase calmodulin affinity for Ca2+ and decrease target affinity for calmodulin
Ohashi, L; Pohoreki, R; Morita, K; Stemmer, PM
Biochimica Et Biophysica Acta-Molecular Cell Research, 1691(): 161-167.
10.1016/j.bbamer.2004.02.001
CrossRef
European Journal of Pain
Nitrous oxide and the inhibitory synaptic transmission in rat dorsal horn neurons
Georgiev, SK; Baba, H; Kohno, T
European Journal of Pain, 14(1): 17-22.
10.1016/j.ejpain.2009.01.008
CrossRef
Anesthesiology
Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat
Dong, HL; Fukuda, S; Murata, E; Higuchi, T
Anesthesiology, 104(1): 122-132.

Journal of Neuroscience Methods
A method for recording single unit activity in lumbar spinal cord in rats anesthetized with nitrous oxide in a hyperbaric chamber
Antognini, JF; Atherley, RJ; Laster, MJ; Carstens, E; Dutton, RC; Eger, EI
Journal of Neuroscience Methods, 160(2): 215-222.
10.1016/j.jneumeth.2006.09.003
CrossRef
Anesthesia and Analgesia
Minimum alveolar anesthetic concentration of isoflurane with different xenon concentrations in swine
Hecker, KE; Reyle-Hahn, M; Baumert, JH; Horn, N; Heussen, N; Rossaint, R
Anesthesia and Analgesia, 96(1): 119-124.
10.1213/01.ANE.0000039189.01536.4C
CrossRef
Life Sciences
Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon
Petzelt, C; Blom, P; Schmehl, W; Muller, J; Kox, WJ
Life Sciences, 72(): 1909-1918.
10.1016/S0024-3205(02)02439-6
CrossRef
Anesthesia and Analgesia
Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats
Culley, DJ; Baxter, MG; Crosby, CA; Yukhananov, R; Crosby, G
Anesthesia and Analgesia, 99(5): 1393-1397.
10.1213/01.ANE.0000135408.14319.CC
CrossRef
British Journal of Anaesthesia
Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones
Dinse, A; Fohr, KJ; Georgieff, M; Beyer, C; Bulling, A; Weigt, HU
British Journal of Anaesthesia, 94(4): 479-485.
10.1093/bja/aei080
CrossRef
British Journal of Anaesthesia
Effects of isoflurane and xenon on Ba2+-currents mediated by N-type calcium channels
White, IL; Franks, NP; Dickinson, R
British Journal of Anaesthesia, 94(6): 784-790.
10.1093/bja/aei126
CrossRef
British Journal of Anaesthesia
Neuroprotective and neurotoxic properties of the 'inert' gas, xenon
Ma, D; Wilhelm, S; Maze, M; Franks, NP
British Journal of Anaesthesia, 89(5): 739-746.

Biochimica Et Biophysica Acta-Biomembranes
Biophysical changes induced by xenon on phospholipid bilayers
Booker, RD; Sum, AK
Biochimica Et Biophysica Acta-Biomembranes, 1828(5): 1347-1356.
10.1016/j.bbamem.2013.01.016
CrossRef
Comprehensive Physiology
Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control
Stuth, EAE; Stucke, AG; Zuperku, EJ
Comprehensive Physiology, 2(4): 2281-2367.
10.1002/cphy.c100061
CrossRef
Anesthesiology
Is Xenon Really Neuroprotective after Cardiac Arrest?
Fries, M; Weis, J; Rossaint, R
Anesthesiology, 104(1): 211.

PDF (398)
Anesthesiology
Computational Aspects of Anesthetic Action in Simple Neural Models
Gottschalk, A; Haney, P
Anesthesiology, 98(2): 548-564.

PDF (1422)
Anesthesiology
Determinants of the Sensitivity of AMPA Receptors to Xenon
Plested, AJ; Wildman, SS; Lieb, WR; Franks, NP
Anesthesiology, 100(2): 347-358.

PDF (773)
Anesthesiology
Chronobiology and Anesthesia
Warltier, DC; Chassard, D; Bruguerolle, B
Anesthesiology, 100(2): 413-427.

PDF (932)
Anesthesiology
Action of Isoflurane on the Substantia Gelatinosa Neurons of the Adult Rat Spinal Cord
Wakai, A; Kohno, T; Yamakura, T; Okamoto, M; Ataka, T; Baba, H
Anesthesiology, 102(2): 379-386.

PDF (809)
Anesthesiology
Xenon Attenuates Cardiopulmonary Bypass–induced Neurologic and Neurocognitive Dysfunction in the Rat
Ma, D; Yang, H; Lynch, J; Franks, NP; Maze, M; Grocott, HP
Anesthesiology, 98(3): 690-698.

PDF (1494)
Anesthesiology
Effect of N-methyl-d-aspartate Receptor ε1 Subunit Gene Disruption of the Action of General Anesthetic Drugs in Mice
Sato, Y; Kobayashi, E; Murayama, T; Mishina, M; Seo, N
Anesthesiology, 102(3): 557-561.

PDF (209)
Anesthesiology
Competitive Inhibition at the Glycine Site of the N-Methyl-d-Aspartate Receptor Mediates Xenon Neuroprotection against Hypoxia–Ischemia
Banks, P; Franks, NP; Dickinson, R
Anesthesiology, 112(3): 614-622.
10.1097/ALN.0b013e3181cea398
PDF (971) | CrossRef
Anesthesiology
Selective Synaptic Actions of Thiopental and Its Enantiomers
Dickinson, R; M. de Sousa, SL; Lieb, WR; Franks, NP
Anesthesiology, 96(4): 884-892.

PDF (1202)
Anesthesiology
The Midlatency Auditory Evoked Potentials Predict Responsiveness to Verbal Commands in Patients Emerging from Anesthesia with Xenon, Isoflurane, and Sevoflurane but Not with Nitrous Oxide
Goto, T; Nakata, Y; Saito, H; Ishiguro, Y; Niimi, Y; Morita, S
Anesthesiology, 94(5): 782-789.

PDF (193)
Anesthesiology
Xenon Exerts Age-independent Antinociception in Fischer Rats
Ma, D; Sanders, RD; Halder, S; Rajakumaraswamy, N; Franks, NP; Maze, M
Anesthesiology, 100(5): 1313-1318.

PDF (1045)
Anesthesiology
Effects of Xenon on In Vitro and In Vivo Models of Neuronal Injury
Wilhelm, S; Ma, D; Maze, M; Franks, NP
Anesthesiology, 96(6): 1485-1491.

PDF (443)
Anesthesiology
Molecular Mechanisms Transducing the Anesthetic, Analgesic, and Organ-protective Actions of Xenon
Preckel, B; Weber, NC; Sanders, RD; Maze, M; Schlack, W
Anesthesiology, 105(1): 187-197.

PDF (1022)
Anesthesiology
Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels
Raines, DE; Claycomb, RJ; Scheller, M; Forman, SA
Anesthesiology, 95(2): 470-477.

PDF (198)
Anesthesiology
Combination of Xenon and Isoflurane Produces a Synergistic Protective Effect against Oxygen–Glucose Deprivation Injury in a Neuronal–Glial Co-culture Model
Ma, D; Hossain, M; Rajakumaraswamy, N; Franks, NP; Maze, M
Anesthesiology, 99(3): 748-751.

PDF (318)
Anesthesiology
Xenon Acts by Inhibition of Non–N-methyl-d-aspartate Receptor–mediated Glutamatergic Neurotransmission in Caenorhabditis elegans
Nagele, P; Metz, LB; Crowder, CM
Anesthesiology, 103(3): 508-513.

PDF (316)
Anesthesiology
Effects of Gaseous Anesthetics Nitrous Oxide and Xenon on Ligand-gated Ion Channels: Comparison with Isoflurane and Ethanol
Yamakura, T; Harris, RA
Anesthesiology, 93(4): 1095-1101.

PDF (284)
Anesthesiology
The Neuroprotective Effect of Xenon Administration during Transient Middle Cerebral Artery Occlusion in Mice
Homi, HM; Yokoo, N; Ma, D; Warner, DS; Franks, NP; Maze, M; Grocott, HP
Anesthesiology, 99(4): 876-881.

PDF (333)
Anesthesiology
The Minimum Alveolar Concentration of Xenon in the Elderly Is Sex-dependent
Goto, T; Nakata, Y; Morita, S
Anesthesiology, 97(5): 1129-1132.

PDF (134)
Anesthesiology
Positron Emission Tomography Study of Regional Cerebral Metabolism during General Anesthesia with Xenon in Humans
Rex, S; Schaefer, W; Meyer, PH; Rossaint, R; Boy, C; Setani, K; Büll, U; Baumert, JH
Anesthesiology, 105(5): 936-943.

PDF (1996)
Anesthesiology
Noble Meets Nouveau: A Shared Anesthetic Binding Site for Xenon and Isoflurane on a Glutamate Receptor
Hemmings, HC
Anesthesiology, 107(5): 694-696.
10.1097/01.anes.0000287289.03790.1b
PDF (261) | CrossRef
Anesthesiology
Competitive Inhibition at the Glycine Site of the N-Methyl-d-aspartate Receptor by the Anesthetics Xenon and Isoflurane: Evidence from Molecular Modeling and Electrophysiology
Martin, JC; Valenzuela, CA; Maze, M; Franks, NP; Dickinson, R; Peterson, BK; Banks, P; Simillis, C
Anesthesiology, 107(5): 756-767.
10.1097/01.anes.0000287061.77674.71
PDF (1626) | CrossRef
Anesthesiology
Xenon and the Pharmacology of Fear
Hemmings, HC; Mantz, J
Anesthesiology, 109(6): 954-955.
10.1097/ALN.0b013e31818d4964
PDF (84) | CrossRef
Anesthesiology
Xenon Reduces N-Methyl-d-aspartate and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor–mediated Synaptic Transmission in the Amygdala
Haseneder, R; Kratzer, S; Kochs, E; Eckle, V; Zieglgänsberger, W; Rammes, G
Anesthesiology, 109(6): 998-1006.
10.1097/ALN.0b013e31818d6aee
PDF (1399) | CrossRef
Anesthesiology
Xenon Attenuates Excitatory Synaptic Transmission in the Rodent Prefrontal Cortex and Spinal Cord Dorsal Horn
Haseneder, R; Kratzer, S; Kochs, E; Mattusch, C; Eder, M; Rammes, G
Anesthesiology, 111(6): 1297-1307.
10.1097/ALN.0b013e3181c14c05
PDF (1278) | CrossRef
Critical Care Medicine
The neuroprotective effects of xenon and helium in an in vitro model of traumatic brain injury*
Coburn, M; Maze, M; Franks, NP
Critical Care Medicine, 36(2): 588-595.
10.1097/01.CCM.0B013E3181611F8A6
PDF (1058) | CrossRef
Journal of Clinical Neurophysiology
Understanding the Transition to Seizure by Modeling the Epileptiform Activity of General Anesthetic Agents
Liley, DT; Bojak, I
Journal of Clinical Neurophysiology, 22(5): 300-313.

PDF (1881)
Back to Top | Article Outline
Keywords:
Analgesia; anesthesia; autapses; ligand-gated channels; noble gases.

© 2000 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.