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ANESTHETIC PHARMACOLOGY

Gamma-Aminobutyric Acid_A Receptors Do Not Mediate the Immobility Produced by Isoflurane

Yi Zhang, MD^*, James M. Sonner, MD, Edmond I Eger, II, MD^*, Caroline R. Stabernack, MD^*, Michael J. Laster, DVM^*, Douglas E. Raines, MD, and R. Adron Harris, PhD

*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, Harvard Medical School, Boston, Massachusetts, and the University of Texas, Austin, Texas

Address correspondence and reprint requests to James M. Sonner, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143–0464. Address email to sonnerj{at}anesthesia ucsf.edu.

	Abstract

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Many inhaled anesthetics enhance the effect of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), supporting the view that the GABA_A receptor could mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation (i.e., MAC, the minimum alveolar concentration required to suppress movement in response to a noxious stimulus in 50% of subjects). However, only limited in vivo data support the relevance of the GABA_A receptor to MAC. In the present study we used two findings to test for the relevance of this receptor to immobilization for isoflurane: 1) differences among anesthetics in their capacity to enhance the response of receptor expression systems to GABA: isoflurane (considerable enhancement), xenon (minimal enhancement), and cyclopropane (minimal enhancement); and 2) studies showing that the spinal cord mediates MAC for isoflurane. If GABA_A receptors mediate isoflurane MAC, then their blockade in the spinal cord should increase isoflurane MAC more than cyclopropane or xenon MAC and the MAC increase should be proportional to the in vitro enhancement of the GABA_A receptor. To test this thesis, isoflurane, cyclopropane, or xenon MAC was determined in rats during intrathecal infusion of artificial cerebrospinal fluid (aCSF) via chronically implanted catheters. Then MAC was redetermined during infusion of 1 µL/min aCSF containing either 0.6 or 2.4 mg/mL picrotoxin, which noncompetitively blocks GABA_A receptors. There was no consistent increase in MAC consequent to increasing the picrotoxin dose from 0.6 to 2.4 µg/min, which suggests that maximal blockade of GABA_A receptors in the spinal cord had been achieved. Picrotoxin infusion increased MAC approximately 40% with all anesthetics. This indicates that GABA release in the spinal cord influences anesthetic requirement. However, the increase did not consistently differ among anesthetics and did not correlate with in vitro enhancement of GABA_A receptors by these anesthetics. This supports the view that GABA_A receptors do not mediate immobilization for isoflurane.

IMPLICATIONS: Although in vitro studies demonstrate that isoflurane enhances the effect of gamma aminobutyric acid (GABA) on GABA_A receptors, results from the present in vivo work indicate that the GABA_A receptor does not mediate the immobility produced by isoflurane.

	Introduction

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Results from studies in various in vitro receptor expression systems reveal actions of inhaled anesthetics on ligand-gated ion and voltage-gated ion channels, as well as on metabotropic receptors. Such results provide plausible molecular explanations for the anesthetic state. Gamma aminobutyric acid (GABA)_A receptors are among the most intensively studied receptors proposed to mediate anesthesia. As of July 2002, 526 publications connect GABA and anesthesia, and 81 of these specifically link GABA_A receptors to anesthesia. Many inhaled anesthetics enhance GABA_A responses to GABA at doses of approximately 1 MAC (the minimum alveolar concentration of anesthetic that eliminates movement in response to a noxious stimulus in 50% of subjects). Some injected anesthetics act (apparently) exclusively on GABA_A (i.e., an action on such receptors alone may be sufficient to produce anesthesia). Thus, the thesis that part or all of the anesthetic effects of inhaled anesthetics result from their capacity to enhance the action of GABA on GABA_A receptors seems tenable, if not directly demonstrated in animals (1).

Isoflurane produces immobility predominantly by an action on the spinal cord (2–4). If GABA_A receptors mediate the capacity of isoflurane to cause immobility, intrathecal application of the chloride channel blocker picrotoxin, which antagonizes primarily GABA_A receptors (and can also antagonize homomeric glycine receptors, a neonatal form of the glycine receptor), should increase the MAC of isoflurane. Consistent with this prediction, we demonstrated a maximum 40% increase in the MAC of isoflurane during the continuous intrathecal administration of picrotoxin (5). Although these results may appear to suggest that GABA_A receptors mediate a portion of the immobility produced by isoflurane, another interpretation is possible: blockade of GABA_A activity may influence immobility indirectly. Blockade of a tonic output of GABA at GABA_A receptors would decrease inhibitory activity and thereby increase MAC, irrespective of whether anesthetic enhanced GABA_A receptor function.

Several reports enable a test of these two possibilities. In vitro studies of xenon (Xe) (6,7) and cyclopropane (8) indicate that these anesthetics minimally enhance the effect of GABA on GABA_A receptors. A drug that blocks GABA_A receptors (picrotoxin) should differently affect animals anesthetized with a drug that does not or minimally affects GABA_A receptors (Xe, cyclopropane) compared with one that does (isoflurane). That is, if spinal GABA_A receptors mediated isoflurane-induced immobility but not Xe- or cyclopropane-induced immobility, then the increase in MAC of rats receiving isoflurane and intrathecal picrotoxin should exceed the increase in MAC of rats receiving Xe or cyclopropane and intrathecal picrotoxin.

We applied this reasoning previously in a study examining the importance of glycine receptors as mediators of the capacity of inhaled anesthetics to produce immobility (9). That study provides a positive control for the current study of GABA_A receptors. In rats, we found that intrathecal infusion of the glycine receptor blocker strychnine increased the MAC of cyclopropane, isoflurane, and halothane and that the increase in MAC correlated closely with the relative capacities of these anesthetics to enhance the in vitro response of glycine receptors.

The null hypothesis of this study was that, using MAC as the anesthetic end-point and spinal application of picrotoxin to antagonize anesthetic effects on spinal GABA_A receptors, there would be no difference in GABA_A effect revealed by intrathecal administration of picrotoxin among Xe, cyclopropane, and isoflurane. That is, we conjectured that (in contrast to the results with glycine receptors) the increase in MAC would not correlate with the in vitro enhancement of GABA_A receptor responses to GABA by these anesthetics.

	Methods

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With approval of the Committee on Animal Research of the University of California, San Francisco, we studied male Sprague-Dawley rats (Crl:CD(SD)BR) weighing 300–450 g obtained from Charles River Laboratories (Hollister, CA).

Rats were anesthetized with isoflurane, and a 32-gauge polyurethane catheter (Micor Inc., Allison Park, PA) was placed through the atlantooccipital membrane following the method of Yaksh and Rudy (10). The catheter was threaded caudally 6 to 8 cm towards the lumbar sac, the length depending on the size of the rat. At the neck, sutures were used to fix the catheter to adjacent muscle and skin. Rats were allowed to recover from anesthesia and surgery for at least 2 days before study.

MAC was determined in two rats simultaneously. Each rat was placed in a clear plastic tube closed at the distal end with a rubber stopper pierced with several holes. A rectal temperature probe and the rat’s tail were drawn through two of these holes. Four 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 Xe, for sampling gases, and for a connection to the intrathecal catheter. The temperature probe and electrodes were connected to electrical pass-throughs, and the catheter to an external catheter connected, in turn, to an infusion pump. The dead space volume of the intrathecal and connecting catheters for both the isoflurane and Xe studies equaled approximately 17 µL. The electrodes were used to stimulate the tail in lieu of the tail clamp; this approach produces the same MAC as with the tail clamp (11). After flushing with oxygen to produce an exiting partial pressure >95% of an atm, the chamber was sealed and the pressure brought to one atm.

For the studies of Xe, the anesthetic then was introduced to approximately 1 atm (2 atm total pressure) and equilibration continued for 30 min. Electrical stimulation to the tail was applied for 1 min or until the animal moved. The Xe concentration then was measured by gas chromatography and corrected to a partial pressure by accounting for the total pressure in the pressure chamber. If the animal moved, the Xe partial pressure was increased by 0.15–0.3 atmospheres. After equilibration for 30 min, the electrical stimulation was applied again and Xe partial pressure measured by chromatography. This procedure was repeated until the partial pressures bracketing movement and nonmovement were determined for each rat.

For the studies of cyclopropane, approximately 2.7 psig (0.18 atm) of the anesthetic was introduced and equilibration continued for 30 min. The remainder of the study was conducted as for Xe except that pure cyclopropane was added with a 100-mL syringe in total volumes of 100 to 160 mL. For isoflurane, approximately 0.01 atm isoflurane was introduced and equilibrium continued for 30 min. As with Xe and cyclopropane, successive increases in isoflurane partial pressure were applied with 30 min of equilibration at each step.

Each study consisted of two parts. In the first, we infused artificial cerebrospinal fluid (aCSF). The aCSF was made daily from stock solutions. Stock solution #1 was a mono-valent stock solution made by adding NaCl 3.6963 g, NaHCO₃ 1.1551 g, KCl 0.0895 g, KH₂PO₄ 0.0340 g, and Na₂SO₄ 0.0355 g in deionized, distilled water to a volume of 500 mL. Stock solution #2 was a di-valent solution made from CaCl₂ · 2H₂O 0.8086 g and MgCl₂ · 6H₂O 0.8437 g in deionized, distilled water to a volume of 10 mL. To make aCSF, 25 mL stock solution #1 was added to 0.0266 g glucose, adjusted to pH 7.4 with bubbles of CO₂ for about 10 min, and added to 50 µL di-valent stock solution.

In the second part, we infused aCSF to which we added the GABA_A blocker picrotoxin (Sigma Chemical, St. Louis, MO). All intrathecal infusions were at a rate of 1 µL/min to limit spread of agent in the subarachnoid space.

We allowed 1 h between the first and second parts of the study, during which time the anesthetic partial pressures were maintained at levels that permitted each rat to respond to the tail clamp or electrical stimulation. For the animals in the present study, picrotoxin was infused at 0.6 and (in separate studies) 2.4 µg/mL (i.e., 4.0 nM/min and 16 nM/min). In the studies of isoflurane, these doses produced a maximum (ceiling) effect (i.e., further increases in dose did not further increase isoflurane MAC) (5). These doses had been shown not to produce toxic effects that changed MAC when tested 2 days after picrotoxin infusion.

To determine the extent of spread of solutions infused at 1 µl/min via intrathecal catheter, 0.025% methylene blue in aCSF was coinfused with picrotoxin in all rats. We previously established that this dose of methylene blue did not affect isoflurane MAC, when infused with aCSF containing or not containing picrotoxin. The extent of spread of the methylene blue was determined visually on necropsy of the animals.

MAC was defined as the average of the partial pressures that just prevented and permitted movement in response to clamping the tail. The change in MAC was calculated as the ratio of the MAC for the second part of each study to the first part. We calculated the mean and SD for the change at each dose of each antagonist. We also analyzed a subset of our data using logistic regression to compute an anesthetic ED₅₀ (MAC) and standard error to confirm that the results obtained by this approach were the same as averaging the MAC for individual animals.

We used a Gow-Mac gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) equipped with a flame ionization detector to measure isoflurane and cyclopropane concentrations. The 4.6 m-long, 0.22 cm (inner diameter) column was packed with SF-96. The column temperature was 138°C–151°C. The detector was maintained at temperatures approximately 50°C warmer than the column. The carrier gas flow was nitrogen at a flow of 15–20 mL/min. The detector received 35–38 mL/min hydrogen and 240–320 mL/min air. Primary standards were prepared for isoflurane and cyclopropane, and the linearity of the response of the chromatograph was determined. We commonly used secondary (cylinder) standards referenced to primary standards for isoflurane and primary (volumetric) standards, only, for cyclopropane.

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

Two of the authors (RAH and DER) provided unpublished data for the responses of GABA_A receptors expressed in individual Xenopus oocytes to submaximal concentrations of GABA (concentrations that produced <20% of the maximum response) at various partial pressures of cyclopropane and isoflurane, and at a single (approximately 0.3 MAC) partial pressure of Xe. Average results for these data (as opposed to the data for individual oocytes) have been published elsewhere (7,8,12). These were used to define the relationship of anesthetic partial pressure and in vitro percent potentiation. This relationship was used to test whether a correlation existed between in vitro enhancement and MAC increase.

The changes in MAC were compared using a one-way analysis of variance. P < 0.05 was taken as significant. MAC changes were also correlated with percent potentiation using least squares regression. The study was designed to have a power of more than 0.95 to detect a change in MAC of 20% (e.g., from 40% to 60%) at the 0.05 significance level, given a standard deviation of 10 in the percentage change in MAC measurements. For purposes of power calculation, the sample size was taken as 20 animals in the "minimally GABAergic" anesthetic group (Xe and cyclopropane), and as 8 animals in the "GABAergic" anesthetic group (isoflurane).

	Results

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MAC increased for all anesthetics (Table 1; Fig. 1). At an infusion of 0.6 µg/min picrotoxin, the increases in MAC did not differ among the anesthetics (P = 0.3). At an infusion of 2.4 µg/min picrotoxin, the increases in MAC also did not differ among anesthetics (P = 0.8). Thus, the null hypothesis that there was no difference among anesthetics could not be rejected. Necropsy revealed methylene blue staining only of the upper lumbar and lower-mid thoracic portions of the spinal cord.

View larger version (17K): [in this window] [in a new window]   Figure 1. The intrathecal infusion of either 0.6 µg/min or 2.4 µg/min picrotoxin increased MAC for isoflurane, xenon, and cyclopropane. The increase did not differ among anesthetics at 0.6 µg/min or at 2.4 µg/min. The change in percentage increase in MAC from 0.6 µg/min to 2.4 µg/min was significant for xenon but not for isoflurane or cyclopropane (P < 0.05). Values are presented as mean ± SD. Data for the three anesthetics are offset on the x-axis for clarity.

The increase in MAC at 2.4 µg/min picrotoxin tended to be larger than at 0.6 µg/min picrotoxin. This difference was not significant for isoflurane (P = 0.2) or cyclopropane (P = 0.5) but did reach significance for Xe (P = 0.03).

In vitro increases in anesthetic partial pressure increased the response of GABA_A receptors to GABA (Fig. 2). The data for isoflurane from DER correlated closely with that from RAH, and the percent potentiation = 58 times e^1.5MAC (r² = 0.82). DER found a greater response to cyclopropane than did RAH, but even with this difference, both found that the effect of isoflurane at a given MAC multiple in the 1–2 MAC range was an order of magnitude greater than the effect of cyclopropane. The percent potentiation = 2.1 time e^0.49MAC (r² = 0.48). A single point for Xe was available, providing a 15% potentiation at 30%–40% of MAC.

View larger version (15K): [in this window] [in a new window]   Figure 2. An increase in the partial pressure of cyclopropane (squares) or isoflurane (circles) increases the percentage potentiation of GABAA receptors in individual Xenopus oocytes [unpublished data from DER (filled symbols) and RAH (open symbols)]. However, at a given MAC value, the increase with isoflurane is more than 10 times larger with isoflurane.

View larger version (31K): [in this window] [in a new window]   Figure 3. The percent increase in MAC produced by the intrathecal infusion of 1 µL/min of 0.6 µg/mL or 2.4 µg/mL of picrotoxin does not correlate with the in vitro percentage potentiation of GABAA receptors as defined by the data in Figure 2.

	Discussion

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To isolate the potentiating effect of isoflurane on GABA_A receptors, xenon and cyclopropane were studied. Xe and cyclopropane have been reported to minimally enhance the effect of GABA on GABA_A receptors. In principle, the change in MAC for Xe and cyclopropane versus the change in MAC for isoflurane from intrathecal infusion of picrotoxin should reflect the difference in the effect of those anesthetics on spinal GABA_A receptors. Our results show no difference among the anesthetics in the antagonism of MAC by 0.6 µg/min or 2.4 µg/min picrotoxin. Because Xe and cyclopropane only minimally enhance GABA_A receptor response in vitro, we conclude that the enhancing action of isoflurane at GABA_A receptors is no more important to the immobilizing action of isoflurane than of cyclopropane or Xe. That is, GABA_A receptors are unlikely to mediate isoflurane-induced immobility as measured by MAC.

We considered several reasons why isoflurane might not produce a larger increase in MAC than Xe or cyclopropane.

First, reports suggesting a failure of Xe to enhance the in vitro effect of GABA applied relatively low partial pressures of Xe, 0.6–0.8 atmospheres (6,7). A more recent report suggests that this finding may not apply at one atmosphere of Xe (13). One atmosphere of Xe is less than that required for anesthesia in rats, and higher (anesthetizing) partial pressures of Xe may supply the same enhancement as anesthetizing partial pressures of isoflurane (see Results). If so, this might explain the similarity of the isoflurane and Xe data. However, the in vitro effect of cyclopropane was tested at 2 MAC, and thus the isoflurane versus cyclopropane argument still holds.

Second, did our infusion of picrotoxin produce a maximal blockade of GABA_A receptors in the lumbar-lower thoracic spinal cord? Because we find no consistent effect on MAC in the present study or in our previous report (5) of increasing the infusion rate of picrotoxin from 0.6 µg/min to 2.4 µg/min, a maximal effect on GABA_A receptors was most likely achieved. However, we cannot exclude the possibility that GABA_A receptors deep within the cord may have escaped blockade at all infusion rates. Though unlikely, it is possible that the picrotoxin did not diffuse the 0.1 mm needed to reach such receptors. This effect should, however, equally affect all three anesthetics.

Third, one might imagine physiologic antagonism of GABA_A receptors in studies with cyclopropane and Xe of exactly the same size as the pharmacologic and physiologic antagonism of GABA_A receptors by isoflurane, if there were separate neuronal circuitry underlying immobility for the different anesthetics. In our view this too is unlikely, although it is possible. The finding that picrotoxin antagonizes the ED₅₀ of ketamine similar to isoflurane (a nonGABAergic anesthetic) and severalfold less than propofol (a GABAergic anesthetic) (14) further suggests isoflurane’s immobilizing action is nonGABAergic

Other evidence supports our conclusion that the GABA_A receptor does not materially mediate the capacity of inhaled anesthetics to cause immobility during noxious stimulation. MAC for fluorinated alkanols (15) bears no consistent relationship to the capacity of those alkanols to enhance the effect of GABA on GABA_A receptors (16). Mutations of the GABA_A receptor (absent the ß-3 subunit) produce small and inconsistent decreases in the MAC of inhaled anesthetics (17) despite severely impairing survival and function of the mutant mice.

Xe, cyclopropane, and isoflurane are not the only anesthetics showing considerable differences in their capacities to potentiate the effect of GABA. At a given MAC-multiple, enflurane, halothane, and isoflurane differ in their enhancement of chloride conductance secondary to application of GABA to rat hippocampal neurons; enflurane is the most potent and halothane is the least potent (18). Similarly, enflurane may be 3 times more potent (as a MAC-multiple) than sevoflurane in its enhancement of current (19). Such variations in potency in vitro have been found in other studies (20). Finally, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane increases GABA release from mouse brain slices stimulated by application of potassium (21). If GABA_A receptors do mediate some of the capacity of inhaled anesthetics to produce immobility, such mediation appears to be anesthetic-dependent and is essentially absent for some anesthetics. Our data suggest that for an anesthetic (isoflurane) for which immobility is spinally mediated and enhancing actions on GABA_A receptors are substantial, those enhancing effects nonetheless contribute little to immobility. This casts doubt on the role of positive modulation of GABA_A receptors to immobility for any anesthetic for which immobility is spinally mediated and enhancement of GABA_A receptors is less than that observed with isoflurane.

	Acknowledgments

 
Supported, in part, by NIGMS 1P01GM47818 and RO1-GM61927.

	Footnotes

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

	References

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