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GENERAL ARTICLES

Both Cerebral GABA_A Receptors and Spinal GABA_A Receptors Modulate the Capacity of Isoflurane to Produce Immobility

Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Address correspondence and reprint requests to James Sonner, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464.

	Abstract

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We previously demonstrated that intrathecal administration of the noncompetitive -aminobutyric acid type A (GABA_A) receptor antagonist picrotoxin increased isoflurane MAC (the minimum alveolar concentration of anesthetic producing immobility in 50% of animals) by a maximum (ceiling effect) of approximately 40%. We also found that IV administration of picrotoxin increased MAC by more than 60%, without evidence of a ceiling effect. The larger increase with IV administration suggested a role of cerebral GABA_A receptors. Accordingly, in this study we examined the effect of intracerebroventricular administration of picrotoxin in rats, finding that picrotoxin infusion into the third ventricle increased isoflurane MAC by a maximum of ap-proximately 40%, without finding a ceiling effect. In addition, we concurrently infused picrotoxin into the intrathecal and intracerebroventricular spaces, producing an increase in MAC in excess of 70%, also with no evidence of a ceiling effect. The dose-response relationship for the intrathecal-intraventricular infusion paralleled that of the IV infusion but was shifted to the left by an order of magnitude. We conclude that both cerebral and spinal GABA_A receptors modulate the capacity of inhaled anesthetics to produce immobility. Because other studies have shown that the spinal cord, and not the brain, mediates the capacity of inhaled anesthetics to produce immobility, these results call into question the relevance of GABA_A receptors to the immobilizing action of isoflurane.

Implications: In rats, cerebral -aminobutyric acid type A (GABA_A) receptors, in addition to spinal GABA_A receptors, influence the immobilizing action of isoflurane but are probably not responsible for that action.

	Introduction

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We previously studied the effect of picrotoxin on isoflurane MAC (the minimum alveolar concentration of anesthetic producing immobility in 50% of animals) (1). We used picrotoxin because it is a noncompetitive -aminobutyric acid type A (GABA_A) receptor antagonist (2), and it therefore allowed us to test the influence of GABA_A receptors on the MAC of isoflurane. This is important because GABA_A receptors have been suggested as a likely molecular site of inhaled anesthetic action (3). Picrotoxin is not perfectly selective for GABA_A receptors: it also antagonizes homomeric glycine receptors, a predominantly fetal form of glycine receptor (4). Although GABA_A and glycine receptors are related and both have also been suggested as targets of anesthetic action (3), in the adult animal, picrotoxin predominantly, though not exclusively, acts on GABA_A receptors.

In our previous study, we demonstrated that the intrathecal administration of picrotoxin increased isoflurane MAC by a maximum (ceiling effect) of approximately 40% (1). We also found that IV administration of picrotoxin increased MAC by more than 60%, without evidence of a ceiling effect. The larger increase with IV administration suggested a role of cerebral GABA_A receptors. The possibility that supraspinal GABA_A receptors might have immobilizing effects was intriguing because it would create a conflict between two current theories of anesthetic action. One theory, based on experiments in animals, suggests that isoflurane exerts its immobilizing action primarily by an action on the spinal cord (5–8). A second theory holds that actions of isoflurane on GABA_A receptors are an important cause of immobility (3,9). Because both spinal and supraspinal GABA_A receptors will be potentiated by isoflurane in an animal inhaling isoflurane, for both theories to be correct only spinal GABA_A receptors should influence the immobilizing effect of isoflurane. Consequently, in this study we examined the capacity of cerebral GABA_A receptors to influence MAC by using cerebral intraventricular administration of picrotoxin in rats.

	Methods

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With approval of the Committee on Animal Research of the University of California, San Francisco, we studied 68 male Sprague-Dawley rats [Crl:CD^®(SD)Br] weighing 300–450 g obtained from Charles River Laboratories (Hollister, CA). Under anesthesia with isoflurane, a 25-gauge stainless steel guide cannula was inserted into either or both lateral ventricles, the third ventricle, or all of these. For placement into the lateral ventricle, the skull was exposed and a hole drilled 0.5 mm posterior to the bregma and 1.5 mm lateral from the midline. A 25-gauge stainless steel guide cannula was placed through the hole to a depth of 4.2 mm from the surface of the skull. For placement into the third ventricle, the skull was exposed and a hole drilled 0.8 mm posterior to the bregma in the midline. The guide cannula was placed through the hole to a depth of 5.0 mm from the surface of the skull. Each cannula was secured by wiring to two screws placed into the skull approximately 5 mm to either side of the cannula. Rats were allowed to recover for a minimum of 24 h before subsequent study.

For some studies, intrathecal catheters were placed at the same time as the guide cannula was placed in the third ventricle. A 32-gauge polyurethane catheter (Micor Inc., Allison Park, PA) was placed through the atlantooccipital membrane by the method of Yaksh and Rudy (10). The catheter was threaded caudally 6 to 8 cm toward 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 24 h before study.

MAC was determined in four rats at a time. Each rat was placed in a gas-tight clear plastic cylinder. A rectal temperature probe was inserted, and the temperature probe and the tail of the rat were separately drawn through holes in the rubber stopper used to seal one end of the cylinder. Ports through the rubber stoppers in each end of the cylinder allowed delivery of gases. The gases entered at the head end of the cylinder and exited at the tail. A total flow rate of 4 L/min of oxygen and isoflurane was delivered to all four cylinders, and the exiting gases were scavenged.

To determine MAC, isoflurane was introduced into the system via a conventional vaporizer, starting with a partial pressure of about 1.0% of an atmosphere. Anesthetic partial pressures were monitored with an infrared analyzer (Datascope, Helsinki, Finland). Animals were equilibrated with the isoflurane partial pressure for 30 min. After 30 min, a tail clamp was applied for 1 min or until the animal moved. The isoflurane partial pressure was then measured by gas chromatography. If the animal moved, the isoflurane partial pressure was increased by 0.1% to 0.2% atm. After equilibration for 30 min, the tail clamp was applied again and isoflurane partial pressure mea-sured. This procedure was repeated until a partial pressure at which the animals did not move was achieved.

Each study was composed of two parts (two determinations of MAC). In the first determination of MAC, we infused artificial cerebrospinal fluid (aCSF) alone at 1 µL/min through a 32-gauge stainless steel blunt-end needle inserted into the guide cannula and (during studies of intrathecal infusion) 1 µL/min through the intrathecal catheter. The aCSF was made daily from stock solutions, with the pH adjusted by bubbling CO₂ through it. The final composition of the aCSF was 154.7 mM Na⁺, 0.82 mM Mg²⁺, 2.9 mM K⁺, 132.49 mM Cl^-, 1.1 mM Ca²⁺, and 5.9 mM glucose, at a pH of 7.4. In the second study, we infused aCSF to which we added picrotoxin (Sigma Chemical Co., St. Louis, MO). Infusions were at a rate of 1 to 8 µL/min. At the largest concentrations of picrotoxin (2.4 mg/mL), we increased the partial pressure of carbon dioxide in the aCSF, producing pH values as low as 6.0, to promote solvation of the picrotoxin.

In the second part of the study, the aCSF was replaced with aCSF containing picrotoxin and 0.025% methylene blue. The interval between the first and second parts of the study was a half-hour, during which time the isoflurane concentration was decreased to the point that each rat again responded to the tail clamp.

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 percentage of increase in the MAC for the second part of each study relative to the first part. We calculated the mean and SD for the change at each dose of picrotoxin.

Several control experiments were performed in which MAC was determined. In four rats we infused aCSF alone into the third ventricle at 4 µL/min. In four rats we infused 0.05% methylene blue alone into the third ventricle at 4 µL/min. In eight rats, 0.6 µg/min picrotoxin was infused into one lateral ventricle at 1 µL/min. In four rats, 0.6 µg/min picrotoxin was infused into both lateral ventricles at 0.5 µL/min to each ventricle. These results were compared with those obtained infusing 0.6 µg/min picrotoxin into the third ventricle at 1 µL/min. The increases in isoflurane MAC associated with picrotoxin infusion did not differ among these studies, and all subsequent studies were conducted with infusions into the third ventricle.

Five studies were conducted with infusions into the third ventricle. In the first three, we infused 1 µL/min of aCSF containing 0.6, 1.2, and 2.4 mg/mL picrotoxin (four rats per dose). In the succeeding two studies, the concentration of picrotoxin was maintained at 2.4 mg/mL (the maximum concentration of picrotoxin that could be dissolved), and the infusion rate was increased to 2 µL/min (four rats) and 4 µL/min (12 rats).

In one study we examined the effect of concurrent infusion of picrotoxin 2.4 mg/mL into the third ventricle at 1, 2, and 4 µL/min, and concurrently 2.4 mg/mL into the intrathecal space at 1, 2, and 4 µL/min, respectively.

Finally, in two studies of four rats each, we examined the effect of infusion of 2.4 mg/mL picrotoxin at an inflow of 8 µL/min into the third ventricle or the left lateral ventricle. In these studies, a second cannula in the unperfused ventricle was placed and left open to allow the venting of excess fluid and to thereby minimize any increase in pressure consequent to infusion at 8 µL/min.

All rats were permitted to awaken to the point where it could be determined that they could move all extremities. They then were killed by inhalation of CO₂. Necropsy was performed to determine the correctness of cannula placement and the extent of staining by methylene blue.

We used a Gow-Mac 750 flame ionization detector gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ). The 4.6-m-long, 0.22-cm (inner diameter) column was packed with SF-96. The column temperature was 138°C. The detector was maintained at temperatures approximately 50°C warmer than the column. The carrier gas flow was nitrogen at a flow rate of 15 mL/min. The detector received 38 mL/min hydrogen and 240 mL/min air. Primary standards were prepared for isoflurane and the linearity of the response of the chromatograph determined. We often used secondary (cylinder) standards referenced to primary standards.

Mean and SD values were calculated, and Student’s t-tests was performed when appropriate. To determine whether a ceiling effect in MAC had been reached, a one-way analysis of variance was performed. A Student-Newman-Keuls test was then used to determine differences in MAC for different doses of antagonist. There was a ceiling effect if successively larger doses of picrotoxin producing the greatest change in MAC were not significantly different from one another. P < 0.05 was taken as statistically significant.

	Results

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All infusions of picrotoxin into the lateral or third ventricles significantly increased MAC (Fig. 1; results for intrathecal and IV infusions are from a previous study) (1). The percentage of increase in MAC did not differ as a function of the site of infusion (one lateral ventricle or both lateral ventricles versus the third ventricle). An increase in infusion rate (i.e., an increase in dose) increased MAC by approximately 40% with no clear evidence of a ceiling effect (Fig. 1). At the fastest infusion rate (4 µL/min), 5 of the 12 rats died during the second determination of MAC. The data for these rats are not included in Table 1. There were significant differences between one or more of the percentage increases at the largest three doses versus the percentage at the smaller doses. When picrotoxin was infused concurrently into both the intrathecal and intracerebroventricular spaces, MAC increased more than the maximum found with either alone (Fig. 1). The intracerebroventricular infusions and combined infusions produced parallel and overlapping dose-response relationships that were shifted to the left of the IV dose-response curve by approximately an order of magnitude. Similarly, the intrathecal infusion resulted in a dose-response curve shifted to the left of the intracerebroventricular infusions and combined infusions by an order of magnitude.

View larger version (27K): [in this window] [in a new window]   Figure 1. Intrathecal, intracerebroventricular, and IV infusion of picrotoxin produce a dose-related increase in isoflurane MAC (the minimum alveolar concentration of anesthetic producing immobility in 50% of animals) of rats. Separate intrathecal and intracerebroventricular infusions increase MAC by a maximum of 40%. A ceiling effect is found with intrathecal infusion, but not with the intracerebroventricular infusion. A combined intrathecal and intracerebroventricular infusion produces a maximum increase in MAC of 70%, an increase similar to that produced by the IV infusion (approximately 60%). No apparent ceiling occurred with either the combined infusion or the IV infusion. Picrotoxin is approximately 10 times more potent when infused intrathecally than when it is infused into the third cerebral ventricle, and it is approximately 10 times more potent when infused into the third ventricle than when infused IV. Data for intrathecal and IV infusions are from a previous study (1).

	Discussion

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The issue addressed in this study is how much picrotoxin influences isoflurane MAC when it is applied intracerebroventricularly, and how that compares with its effect when it is given intrathecally or IV. The effect of picrotoxin is important because it antagonizes GABA_A receptors. These receptors are thought to be important to the anesthetic action of isoflurane (3).

For intrathecal picrotoxin, the maximum effect is defined by the ceiling effect that is observed at the largest doses. We know that picrotoxin reaches its site of action in the spinal cord because there is a change in isoflurane MAC. It reaches this site by diffusion from the CSF. Increasing the concentration of picrotoxin in CSF increases its concentration gradient, which in turn by diffusion increases its concentration at its effect site. This is the reason for its steadily increasing effect. The effect plateaus, however, and further increases in picrotoxin dose do not lead to significant changes in MAC. A maximal biologic effect is reached. No greater effect can be produced, regardless of the concentration of the drug at the receptor. That is the salient finding with respect to spinal application of picrotoxin.

By contrast, infusion of picrotoxin into the cerebral ventricles increases isoflurane MAC (Table 1; Fig. 1), but without a ceiling effect. The increase in MAC obtained with infusion into the third ventricle was as large as that obtained with infusion into the lateral ventricles. Thus, it appears that this increase primarily results from blockade of GABA_A receptors surrounding the third or fourth ventricles. The maximum increase in MAC from intracerebroventricular infusion alone equaled the maximum increase we obtained previously while infusing picrotoxin into the intrathecal space (Fig. 1) (1). Both of these are less than the increase obtained when picrotoxin is infused IV (Fig. 1).

However, when picrotoxin is infused into the intrathecal and the intracerebroventricular spaces concurrently, the increase in MAC equals that resulting from IV infusion. Finally, the potency of picrotoxin differs as a function of the three routes of administration: intrathecal is more potent than intracerebroventricular, and intracerebroventricular and combined intracerebroventricular/intrathecal are more potent than IV. The differences of each are approximately an order of magnitude (Fig. 1).

What do these results say regarding the role of GABA_A receptors in anesthesia? Clearly, blockade of such receptors in either the spinal cord or supraspinal centers increases MAC, suggesting that these receptors may play a role. However, such findings do not indicate whether GABA and GABA_A receptors mediate or modulate the effects of inhaled anesthetics. That is, they do not indicate whether the enhancement of GABA_A responses produced by inhaled anesthetics contributes to the immobilizing action of the anesthetic (in which case we would say that GABA receptors mediate a portion of the action of anesthetics) or whether they block input of tonically active GABA_A receptors (i.e., activity independent of the capacity of isoflurane to enhance the GABA_A receptor response to GABA), which would increase anesthetic requirement (in which case we would say the GABA_A receptors modulate the site at which anesthetics truly act). Because picrotoxin blocks both the baseline effect of GABA at GABA_A receptors and the enhancement produced by isoflurane, it necessarily has a much greater effect in its actions on GABA_A receptors than isoflurane. Indeed, the size of the effect produced by picrotoxin on MAC places a limit on what isoflurane, which has only an enhancing action on that receptor, may do. It is certainly plausible that isoflurane may not have a significant effect on that receptor with respect to immobilizing the animal.

Our evidence is consistent with the thought that GABA_A receptors do not mediate the actions of anesthetics. Studies in rats and goats demonstrate that inhaled anesthetics cause immobility by acting on the spinal cord (5–8). In rats, cervical transection of the spinal cord does not change MAC (7). In goats, separate perfusion of the brain and spinal cord (the cord naturally and the brain with extracorporeal circulation) reveals that the cord is more sensitive to anesthetic than the brain. Nearly three times the cerebral concentration of isoflurane is required to prevent pain-evoked movement when the brain alone is perfused with anesthetic compared with perfusion of both the brain and spinal cord (5,6).

Consequently, if GABA_A receptors mediated at least a portion of the effect of anesthetics, then we would have expected to find that intrathecal infusion of picrotoxin would increase MAC but that intraventricular infusion would have no effect or, at least, a much smaller effect. However, if tonic GABA_A activity modulates the overall response of the central nervous system to noxious stimulation, then intraventricular infusion could produce a significant effect or even greater effect than an intrathecal infusion. Our results are consistent with the second of these possibilities.

Our data indicate a consistent capacity of picrotoxin to increase the MAC of isoflurane, regardless of the route of administration (intracerebroventricular, intrathecal, or IV). That is, inhibition of GABA_A receptors increases anesthetic requirement as defined by MAC. Injection of picrotoxin into various central nervous system sites, as well as peripherally, often (but not always) has effects on pain perception. However, the numerous reports on this effect provide often apparently conflicting results (11–14), and thus speculation on the nociceptive effect of picrotoxin on MAC seems unwarranted.

Finally, one potentially confounding factor in our study is the extension of the intracerebroventricular infusion of picrotoxin to the cervical portion of the cord at faster inflow rates. That is, a portion of the effect at those rates may have resulted from an effect on the cord. However, this does not alter the interpretation of the absence of a ceiling effect with the combined infusion—an infusion wherein the intraventricular infusion did not reach the cord. The combined infusion produced an increase in MAC beyond that produced by an intrathecal infusion alone and was parallel to but far more effective (potent) than the effect of an IV infusion.

	Acknowledgments

 
This work was supported by National Institutes of Health grant 1PO1GM47818-07. Baxter Pharmaceuticals donated the isoflurane.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Eger, E. I Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Eger, E. I, II Related Collections Mechanisms Pharmacology

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