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Anesth Analg 2007; 105:1287-1292
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000282829.21797.97
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ANESTHETIC PHARMACOLOGY

Volatile Aromatic Anesthetics Variably Impact Human {gamma}-Aminobutyric Acid Type A Receptor Function

Elizabeth W. Kelly, BA*{dagger}, Ken Solt, MD*{dagger}, and Douglas E. Raines, MD*{dagger}

From the *Department of Anesthesia and Critical Care, Massachusetts General Hospital, and {dagger}Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts.

Address correspondence and reprint requests to Douglas E. Raines, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Clinics Building 3, Boston, MA 02114. Address e-mail to draines{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The {gamma}-aminobutyric acid type A (GABAA) and N-methyl-d-aspartate (NMDA) receptors are important inhibitory and excitatory neurotransmitter receptors, respectively, in the central nervous system. At the concentrations required to produce immobility in the face of a noxious stimulus, volatile aromatic anesthetics inhibit NMDA receptors to varying degrees, strongly suggesting that they also act at other targets to produce immobilization. In this study, we sought to assess the potential role that GABAA receptors play in mediating the behavioral actions of volatile aromatic anesthetics.

METHODS: Electrophysiological techniques were used to quantify the effects of eight volatile aromatic anesthetics and three clinical anesthetics on currents mediated by {alpha}1ß2{gamma}2L GABAA receptors expressed in Xenopus oocytes.

RESULTS: At equivalent minimal alveolar anesthetic concentration multiples, volatile aromatic anesthetics vary widely in the degrees to which they enhance GABAA receptor-mediated currents elicited by low concentrations of GABA. In general, anesthetics that inhibit NMDA receptors most, enhanced GABAA receptors least. This reciprocal relationship between anesthetic potency on GABAA versus NMDA receptors was also observed for the clinical anesthetics isoflurane, halothane, and cyclopropane. Studies using a range of GABA concentrations indicated that volatile aromatic anesthetics enhance GABAA receptor activity by shifting the open-close (gating) equilibrium towards the open channel state.

CONCLUSIONS: These findings suggest that GABAA receptors contribute variably to the behavioral actions of volatile anesthetics and imply that the molecular determinants of anesthetic action on NMDA and GABAA receptors are distinctly different.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The {gamma}-aminobutyric acid type A (GABAA) receptor is distributed throughout the central nervous system and is the major inhibitory neurotransmitter receptor in the brain. It is also a sensitive target of general anesthetics representing a wide range of chemical classes, including alcohols, steroids, halogenated alkanes, and ethers (1–4). At clinically relevant concentrations, nearly all inhaled anesthetics enhance GABAA receptor function, a property that is thought to contribute to their behavioral effects (3,5,6). However, some inhaled anesthetics (e.g., cyclopropane and xenon) minimally affect the function of GABAA receptors at clinically relevant concentrations (7–9). These anesthetics are thought to produce anesthesia, at least in part, by inhibiting excitatory N-methyl-d-aspartate (NMDA) receptors (10–12).

Volatile aromatic compounds, such as benzene and its close structural analogues, form a homologous group of compounds that are widely recognized as inhaled drugs of abuse (13,14). Although not used clinically, they are also general anesthetics; at lower concentrations, they produce dizziness, amnesia, and unconsciousness, and at higher concentrations, they produce immobilization in the face of a noxious stimulus (15–17). Thus, they may be used as pharmacological tools to better understand how and where inhaled general anesthetics act to produce their behavioral effects (18).

Although volatile aromatic anesthetics can inhibit NMDA receptors, the extent of this inhibition varies widely at 1 minimal alveolar anesthetic concentration (MAC) (19). This strongly suggests that these anesthetics also act at other targets to produce immobilization. The objective of the present study was to assess the potential role that GABAA receptors play in mediating the behavioral actions of volatile aromatic anesthetics. To achieve this goal, we studied a set of volatile aromatic anesthetics that vary widely in their NMDA receptor inhibitory potencies and measured their effect on GABAA receptor function using electrophysiological techniques.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Adult female Xenopus laevis frogs (Xenopus One, Ann Arbor, MI) were maintained and treated in accordance with regulations specified by the Massachusetts General Hospital Animal Care Committee and with their approval. Frogs were anesthetized with 0.2% tricaine (ethyl-m-aminobenzoate) and hypothermia. Ovary lobes were then excised through a small laparotomy incision and placed in OR-2 solution (82 mM NaCl, 2 mM KCl, 2 mM MgCl2, 5 mM HEPES, pH 7.5) containing collagenase 1A (1 mg/mL) for 3 h to separate oocytes from connective tissue.

Stage 4 and 5 oocytes were injected with mRNA encoding the {alpha}1, ß2, and {gamma}2L subunits of the human GABAA receptor (approximately 40 ng of mRNA total at a subunit ratio of 1:1:2). This mRNA was transcribed from cDNA encoding for GABAA receptor {alpha}1, ß2, and {gamma}2L subunits (kindly provided by Dr. Stuart Forman, Massachusetts General Hospital) using the mMESSAGE mMACHINE High Yield Capped RNA Transcription Kit (Ambion, Austin, TX). Injected oocytes were incubated in ND-96 buffer solution (96 mM NaCl, 2 mM KCl, 1 mM CaCl2, 0.8 mM MgCl2, 10 mM HEPES, pH 7.5) containing 50 U/mL of penicillin and 50 µg/mL of streptomycin at 17°C for at least 18 h before electrophysiological experiments.

All electrophysiological recordings were performed at room temperature (22°C–24°C) using the whole cell two-electrode voltage-clamp technique. Oocytes were placed in a 0.04 mL recording chamber and impaled with capillary glass electrodes filled with 3 M KCl and possessing open tip resistances <5 M{Omega}. Oocytes were then voltage-clamped at –50 mV using a GeneClamp 500B amplifier (Axon Instruments, Union City, CA), and constantly perfused with ND-96 buffer at a rate of 4–6 mL/min using a closed-syringe perfusion system. Buffer perfusion was controlled using a six-channel valve controller (Warner Instruments, Hamden, CT) interfaced with a Digidata 1322A data acquisition system (Axon Instruments, Union City, CA), and driven by a Dell personal computer (Round Rock, TX). Current responses were recorded using Clampex 9.0 software (Axon Instruments, Union City, CA), and processed using a Bessel (8-pole) low-pass filter with a –3 dB cutoff at 1.56 Hz using Clampfit 9.0 software (Axon Instruments, Union City, CA). The perfusion apparatus was made from gastight glass syringes and Teflon tubing to minimize absorptive and evaporative loss of volatile anesthetic drugs. Using gas chromatography, we have found that volatile and gaseous anesthetic loss using this technique is <15%.

Before anesthetic studies to characterize enhancement of agonist-evoked currents, the concentration of GABA that produces 5%–10% of the maximal current response (EC5–10) was determined for each oocyte by measuring the peak current response evoked by a range of GABA concentrations (in ND-96 buffer) and comparing it with the maximal peak current response evoked by 1 mM GABA. To assess the effect of anesthetic on EC5–10 GABA-evoked currents, oocytes were perfused with anesthetic in buffer for 30 s and then with anesthetic plus EC5–10 GABA for 90 s. The resulting peak current response was then normalized to the maximal peak current evoked by a 9 s pulse of 1 mM GABA. To minimize the impact of desensitization on peak current responses, a recovery period of at least 2 minutes was used between experiments. Anesthetic-induced enhancement was quantified from the normalized current responses in the presence versus absence of anesthetic.

The effect of two aromatic anesthetics (fluorobenzene and pentaflurobenzene) on the GABA EC50 for peak current activation was determined as described above, except that a wide range of GABA concentrations was used to evoke GABAA receptor current responses. All currents were normalized to that evoked by 1 mM GABA. The EC50 for peak current activation, the Hill coefficient, and the maximal response at high GABA concentrations were then calculated from the GABA concentration-dependence of the normalized peak current response using the Hill equation.

Direct activation of GABAA receptors by fluorobenzene and pentafluorobenzene was measured by pulsing oocytes expressing {alpha}1ß2{gamma}2L GABAA receptors with anesthetic in ND96 buffer for 3 m. Because the peak current response varies with the level of receptor expression, the anesthetic-elicited current was normalized to that elicited by 1 mM GABA in the same oocyte.

The aqueous concentrations corresponding to 1 MAC (in rats) have been previously reported (19). For each volatile aromatic anesthetic, a stock solution was prepared by weighing the appropriate quantity of anesthetic into a glass bottle and filling the bottle with buffer. The bottle was quickly sealed after filling using a Teflon-coated cap and the solution was vigorously stirred for at least 1 h. Care was taken to minimize the volume of air in the sealed bottle (always <5% of the total bottle volume). Stock solutions were diluted with ND 96 buffer in gastight glass syringes to achieve the desired final anesthetic concentrations. For clinical anesthetics (halothane, isoflurane, and cyclopropane), solutions containing the desired anesthetic concentration were made by diluting saturated stock solutions as previously described (19). All aromatic anesthetics and cyclopropane were purchased from Sigma-Aldrich Chemical Co. (Milwaukee, WI). Halothane and isoflurane were purchased from Halocarbon Laboratories (River Edge, NJ) and Baxter Healthcare Corp. (Deerfield IL), respectively. All data are reported as the mean ± sd. Data were analyzed using Igor Pro 5.04B (Wavemetrics, Lake Oswego, OR) or Prism 4.01 (Graphpad Software, San Diego, CA).


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Representative current traces obtained upon perfusing an oocyte expressing {alpha}1ß2{gamma}2L GABAA receptors with either GABA alone or GABA along with pentafluorobenzene or fluorobenzene are shown in Figure 1. In this figure, the first trace shows the control current evoked by EC5–10 GABA before applying anesthetic. The second trace shows the large enhancing effect (250%) of 2 MAC pentafluorobenzene when applied before and during the agonist pulse. The third trace demonstrates the reversibility of pentafluorobenzene’s actions. The fourth trace shows the relatively small current-enhancing effect (39%) of 2 MAC fluorobenzene and the fifth trace demonstrates the reversibility of fluorobenzene’s actions.


Figure 120
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  		Figure 1. Representative electrophysiological traces comparing the effects of pentafluorobenzene and fluorobenzene on currents evoked by EC5–10 {gamma}-aminobutyric acid (GABA) and mediated by {alpha}1ß2{gamma}2L GABAA receptors. The GABA concentration was 3 µM and the volatile aromatic concentrations were equivalent to 2 MAC in rats. All current traces were obtained using the same oocyte.

 

All eight volatile aromatic anesthetics enhanced GABAA receptor-mediated currents evoked by EC5–10 GABA in a concentration-dependent manner. However, the magnitude of this potentiation varied greatly among anesthetics. For each anesthetic, Figure 2 shows the magnitude of current enhancement produced by anesthetics at concentrations equivalent to 1 MAC or 2 MAC. In this figure (and all others), data points are reported as mean ± sd. At 1 MAC, enhancement ranged from 11% ± 8% (fluorobenzene) to 160% ± 50% (pentafluorobenzene). At 2 MAC, this enhancement ranged from 32% ± 14% (benzene) to 280% ± 40% (pentafluorobenzene).


Figure 220
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  		Figure 2. Volatile aromatic anesthetic potentiation of EC5–10 {gamma}-aminobutyric acid (GABA)-elicited currents mediated by {alpha}1ß2{gamma}2L GABAA receptors. For each anesthetic, data were collected using 3–5 oocytes at each concentration and expressed as the mean ± sd.

 

Previous studies have shown that clinical anesthetics increase the GABAA receptor’s sensitivity to agonist (20,21). To determine whether this mechanism also accounts for the enhancing actions of volatile aromatic anesthetics, we measured currents elicited by a range of GABA concentrations in the absence and presence of a representative anesthetic that greatly enhanced currents (pentafluorobenzene) and one that had relatively little effect (fluorobenzene). In these experiments, each pair of GABA concentration–response curves (control and test) was obtained with the same oocytes to minimize the potentially confounding effects of cell-to-cell-variability. Figure 3 shows that pentafluorobenzene significantly reduced the GABA EC50 for peak current activation from 29.5 ± 2.3 µM to 19.9 ± 2.8 µM (P = 0.0325) and increased the maximal peak current evoked by high GABA concentrations by 20% ± 4% (P = 0.0065). In contrast, fluorobenzene produced no measurable change in either the GABA EC50 for peak current activation or the maximal current evoked by high GABA concentrations.


Figure 320
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  		Figure 3. {gamma}-aminobutyric acid (GABA) concentration-response curves for activation of {alpha}1ß2{gamma}2L GABAA receptor-mediated currents. Panel A shows the effect of pentafluorobenzene (2 MAC) and panel B shows the effect of fluorobenzene (2 MAC). Each data point represents the mean value from three oocytes and the error bars indicate the sd.

 

At high concentrations, many anesthetics also directly activate GABAA receptors in the absence of agonist. Figure 4 shows that pentafluorobenzene and fluorobenzene exhibited distinctly different abilities to directly activate GABAA receptors. The magnitude of the directly activated current increased with pentafluorobenzene concentration before reaching 3.1% ± 0.8% of that elicited by 1 mM GABA at 10 MAC whereas fluorobenzene produced little direct activation even at 10 MAC (0.14% ± 0.06%).


Figure 420
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  		Figure 4. Direct activation of {alpha}1ß2{gamma}2L {gamma}-aminobutyric acid type A (GABAA) receptors by volatile aromatic anesthetics. The inset shows representative current traces elicited by pentafluorobenzene (PFB, left traces) or fluorobenzene (FB, right traces) at 2 and 10 MAC in the same oocyte. Anesthetic concentration-response curves for direct activation are also plotted. The magnitude of each response was normalized to that evoked by 1 mM GABA in the same oocyte. For each anesthetic, data were collected using three oocytes at each concentration and expressed as the mean ± sd.

 

To compare the GABAA receptor enhancing effects of volatile aromatic anesthetics with those of clinical anesthetics, we used clinical anesthetics representing a range of chemical classes: isoflurane (a halogenated ether), halothane (a halogenated alkane), and cyclopropane (a nonhalogenated alkane). At 1 MAC, isoflurane and halothane enhanced EC5–10 GABA-evoked currents by 380% ± 99% and 480% ± 190%, respectively (Fig. 5). At 2 MAC, isoflurane and halothane enhanced such currents by 790% ± 130% and 780% ± 250%, respectively. In contrast, cyclopropane produced no current enhancement at either 1 or 2 MAC (–22% ± 39% and 1% ± 18%, respectively).


Figure 520
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  		Figure 5. Clinical anesthetic enhancement of EC5–10 {gamma}-aminobutyric acid (GABA)-elicited currents mediated by {alpha}1ß2{gamma}2L GABAA receptors. For each anesthetic, data were collected using 4–6 oocytes at each concentration and expressed as the mean ± sd.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Ligand-gated ion channels are widely considered to be among the most important targets of general anesthetics (22–24). In particular, members of the cys-loop superfamily (e.g., GABAA receptors) and glutamatergic superfamily (e.g., NMDA receptors) are thought to be important mediators of anesthetic action, including the ability of anesthetics to produce immobility in the face of a noxious stimulus. In general, anesthetics enhance the activities of inhibitory GABAA receptors and inhibit those of excitatory NMDA receptors.

Previous studies from our group have shown that volatile aromatic anesthetics inhibit NR1/NR2B NMDA receptors with widely varying potencies (25). Subsequent studies indicated that volatile aromatic anesthetics may be divided into two groups based on the magnitude of NMDA receptor inhibition produced at 1 MAC (19); at 1 MAC, benzene, fluorobenzene, and 1,2-difluorobenzene greatly inhibit NMDA receptor currents (64% ± 8.7%) whereas 1,4-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene produce much less NMDA receptor inhibition (18% ± 5.2%). The varied magnitude of NMDA receptor inhibition at a single behavioral end point (immobility) strongly suggests that in addition to inhibiting NMDA receptors, volatile aromatic anesthetics (as a group) also act on other targets.

In this study, we assessed the potential role that GABAA receptors play in mediating the behavioral actions of volatile aromatic anesthetics. We found that volatile aromatic anesthetics vary considerably in the extent to which they modulate the function of {alpha}1ß2{gamma}2L GABAA receptors, the most common GABAA receptor subtype in the brain (26). Studies of pentafluorobenzene and fluorobenzene using a range of GABA concentrations demonstrated that pentafluorobenzene significantly reduces the GABAA receptor’s GABA EC50 for activation, indicative of an increased sensitivity for agonist, whereas fluorobenzene has no measurable effect. Pentafluorobenzene also significantly increases currents elicited by receptor-saturating concentrations of GABA and directly activates receptors, even in the absence of agonist, whereas fluorobenzene has little or no effect. These findings imply that pentafluorobenzene shifts the open-close (gating) equilibrium towards the open channel state, a receptor mechanism that has previously been suggested to account for the agonist-enhancing and direct activating actions of other general anesthetics on GABAA receptors (21,27,28).

Figure 6 compares the extent of anesthetic-induced NMDA receptor inhibition with that of GABAA receptor enhancement at 1 MAC. In general, volatile aromatic anesthetics that inhibit NMDA receptor currents most (Group 1) enhance GABAA receptor currents least. Additionally, volatile aromatic anesthetics that inhibit NMDA receptor currents least (Group 2) enhance GABAA receptor currents most. This suggests that the underlying molecular forces that define the receptor actions of volatile aromatic anesthetics are distinctly different between the NMDA and GABAA receptors. For the NMDA receptor, cation–{pi} interactions appear to be the dominant molecular force that determines the inhibitory potencies of volatile aromatic anesthetics (25). Presumably, other electrostatic and/or steric interactions determine the potencies with which volatile aromatic anesthetics enhance GABAA receptors.


Figure 620
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  		Figure 6. Relationship between the magnitudes of anesthetic-induced agonist enhancement of {alpha}1ß2{gamma}2L {gamma}-aminobutyric acid type A (GABAA) receptors and inhibition of NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. Respectively, Group 1 and Group 2 anesthetics strongly and weakly inhibit NMDA receptors at 1 MAC. The magnitude of NMDA receptor inhibition at 1 MAC is from Solt et al. (19) whereas GABA enhancement data at 1 MAC are from the present study. Volatile aromatic anesthetics are shown as solid circles whereas clinical anesthetics are shown as open circles.

 

Figure 6 also shows that this inverse relationship between the magnitudes of anesthetic action at NMDA and GABAA receptors (at 1 MAC) is exhibited by three structurally diverse clinical anesthetics. Consistent with previous studies, the relatively strong NMDA receptor inhibitor cyclopropane produced no detectable GABAA receptor enhancement, whereas the weaker NMDA receptor inhibitors isoflurane and halothane produced substantial GABAA receptor enhancement. Similarly, the relatively strong NMDA receptor inhibitor, xenon, has been shown to have little effect on the GABAA receptor (7). From this, we infer that the molecular determinants of clinical volatile anesthetic action on NMDA and GABAA receptors are also distinctly different. This is consistent with previous studies showing that the magnitudes of anesthetic action on GABA and glutamate synapses in the hippocampus are agent-specific (29).

In summary, inhaled anesthetics enhance the actions of GABA on GABAA receptors. However, at equivalent MAC multiples, the magnitudes of these actions vary dramatically among anesthetics. In general, we observed that inhaled anesthetics (aromatic and clinical) that inhibit NMDA receptor currents most, enhance GABAA receptor currents least (and vice versa). These findings suggest that GABAA and NMDA receptors contribute variably to the behavioral actions of inhaled anesthetics and imply that the molecular determinants of anesthetic action on NMDA and GABAA receptors are distinctly different.


   Footnotes
 
Accepted for publication July 16, 2007.

Supported, in part, by National Institutes of Health grants P01-GM58448 (to D.E.R.) and T32-GM07592 (to K.S.) and the Foundation for Anesthesia Education and Research.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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