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ANESTHETIC PHARMACOLOGY

Glycine Receptors Mediate Part of the Immobility Produced by Inhaled Anesthetics

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

*Department of Anesthesia and Perioperative Care, University of California, San Francisco; University of Texas, Austin

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

	Abstract

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Many inhaled anesthetics potentiate the effect of glycine on inhibitory strychnine-sensitive glycine receptors in vitro, supporting the view that this receptor could mediate the immobility produced by inhaled anesthetics during noxious stimulation (i.e., would underlie minimum alveolar anesthetic concentration [MAC]). There are quantitative differences between anesthetics in their capacity to potentiate glycine’s effect in receptor expression systems: halothane (most potentiation), isoflurane (intermediate), and cyclopropane (minimal). If glycine receptors mediate MAC, then their blockade in the spinal cord should increase the MAC of halothane more than that of isoflurane and isoflurane MAC more than cyclopropane MAC; the increases in MAC should be proportional to the receptor potentiation produced in vitro. Rats with chronically implanted intrathecal catheters were anesthetized with halothane, isoflurane, or cyclopropane. During intrathecal infusion of artificial cerebrospinal fluid, MAC was determined. Then MAC was re-determined during an infusion of 3, 12, 24, or 48 (isoflurane only) µg/min of strychnine (strychnine blocks glycine receptors) in artificial cerebrospinal fluid. Strychnine infusion increased MAC in proportion to the enhancement of glycine receptors found in vitro. The maximum effect was with an infusion of 12 µg/min. For the combined results at 12 and 24 µg/min of strychnine, the increase in MAC correlated with the extent of in vitro potentiation (r² = 0.82). These results support the hypothesis that glycine receptors mediate part of the immobilization produced by inhaled anesthetics.

IMPLICATIONS: In vitro, halothane potentiates glycine’s effect on strychnine-sensitive glycine receptors more than isoflurane and isoflurane more than cyclopropane. The present in vivo work indicates that antagonism of the glycine receptor with strychnine increases minimum alveolar anesthetic concentration for halothane more than isoflurane and isoflurane more than cyclopropane. Such results support the notion that glycine receptors may mediate part of the immobility produced by inhaled anesthetics.

	Introduction

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Results from studies from in vitro receptor expression systems reveal that inhaled anesthetics potentiate the effect of glycine on glycine receptors (1–7) and do so at doses of approximately 1 minimum alveolar anesthetic concentration (MAC; the concentration that eliminates movement in response to a noxious stimulus in 50% of subjects). Because glycine receptors inhibit neurotransmission, their potentiation might explain the capacity of inhaled anesthetics to produce the anesthetic state. Furthermore, inhaled anesthetics differ in their capacity to potentiate glycine receptors (8). For a given MAC-multiple, halothane produces a greater potentiation than isoflurane, and both of these anesthetics produce a several-fold greater potentiation than cyclopropane (Fig. 1).

View larger version (24K): [in this window] [in a new window]   Figure 1. Increasing minimum alveolar anesthetic concentration (MAC)-multiples of cyclopropane, isoflurane, and halothane produce increasing potentiation of the current through glycine receptors expressed in Xenopus oocytes produced by the application of glycine (8). Each point provides the response of receptors in an individual oocyte. The potentiation produced by isoflurane and halothane at a given MAC exceeded that for cyclopropane.

We hypothesized that if glycine receptors mediate the capacity of an anesthetic to cause immobility, intrathecal application of the glycine receptor blocker strychnine, which antagonizes primarily glycine receptors, should increase the MAC of that anesthetic. Indeed, we previously demonstrated that this was the case (14), finding an increase in isoflurane MAC of 40%–50%. Furthermore, we hypothesized that strychnine should differently affect rats anesthetized with an anesthetic that has less effect than isoflurane on glycine receptors (cyclopropane) compared with one that has a greater effect (halothane). The present report tests this hypothesis.

	Methods

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With approval of the Committee on Animal Research of the University of California, San Francisco, we studied 48 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 atlanto-occipital membrane following the method of Yaksh and Rudy (15). The catheter was threaded caudally 6–8 cm toward the lumbar sac; the length depended 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 1 day 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 the anesthetic, for sampling gases, and for a connection to the intrathecal catheter. The temperature probe and electrodes were connected to electrical passthroughs, and the catheter to an external catheter connected, in turn, to an infusion pump. The dead-space volume of the intrathecal and connecting catheters 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 (16). After flushing with oxygen to produce an exiting partial pressure >95% of an atm, the chamber was sealed and the pressure brought to 1 atm.

The anesthetic was then introduced (gaseous cyclopropane, liquid isoflurane, and halothane) to approximately 0.7 MAC, and 2–4 psi of oxygen was added. Equilibration continued for 30 (cyclopropane and isoflurane) or 40 (halothane) min. Electrical stimulation to the tail (15 volts at 50 hertz) was then applied for 1 min or until the rat moved. The anesthetic concentration was measured by gas chromatography and corrected to a partial pressure by accounting for the total pressure in the pressure chamber. If the rat moved, the anesthetic partial pressure was increased by 0.1–0.2 MAC. After equilibration for 30 or 40 min, the electrical stimulation was applied again, and anesthetic partial pressure was measured by chromatography. This procedure was repeated until the partial pressures bracketing movement/none movement were determined for each rat.

Each study consisted of two parts. In the first, we infused artificial cerebrospinal fluid (aCSF) alone. The stock solutions for aCSF were made up daily, as described previously (14). The final composition of aCSF was 154.7 mM of Na⁺, 0.82 mM of Mg²⁺, 2.9 mM of K⁺, 132.49 mM of Cl^-, 1.1 mM of Ca²⁺, and 5.9 mM of glucose at a pH value of 7.4. In the second part, we infused aCSF, to which we added the glycine blocker strychnine (Sigma Chemical Co., St Louis, MO). Intrathecal infusions were at a rate of 1 µL/min for the slowest two strychnine infusion rates. Solubility limitations mandated the use of 2 or 4 µL/min of strychnine for the fastest two strychnine infusion rates.

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 electrical stimulation. Strychnine was infused at concentrations of 3, 12, 24, or 48 (only isoflurane was studied at 48) µg/min. A dose of 12 µg/mL (12 µg/min) produced a maximum (ceiling) effect (i.e., further increases in dose did not further increase MAC). Only one infusion rate was given per rat.

To confirm that drugs infused at 4 µL/min via an intrathecal catheter remained confined to the spinal subarachnoid space, 0.01% methylene blue in aCSF was concurrently infused with strychnine in these rats. We previously established that this dose of methylene blue did not affect the isoflurane MAC. The extent of spread of the methylene blue was determined visually on necropsy of the rats.

MAC was defined as the average of the partial pressures that just prevented and permitted movement in response to electrical stimulation of 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 compared the increases in MAC among the three anesthetic groups using a one-way analysis of variance (ANOVA).

We used a Gow-Mac gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) equipped with a flame ionization detector to measure isoflurane, halothane, and cyclopropane concentrations. The 4.6-m-long, 0.22-cm (infective dose) 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 rate of 15–20 mL/min. The detector received 35–38 mL/min of hydrogen and 240–320 mL/min of air. Primary standards were prepared for each anesthetic, and the linearity of the response of the chromatograph was determined. We often used secondary (cylinder) standards referenced to primary standards for isoflurane and halothane and primary (volumetric) standards only for cyclopropane.

The relationship between potentiation of the glycine receptor and MAC fraction was determined by linear regression. Using the equations obtained in Figure 1, we determined the percentage potentiation that would be achieved in vitro for each of the increases in MAC determined in vivo for each rat for each anesthetic. We then correlated the increases in MAC for all anesthetics at infusion rates of 12 and 24 µg/min of strychnine as a function of the in vitro potentiation specific to a given anesthetic and MAC-multiple.

The increases in MAC at a given infusion rate of strychnine were compared using a one-way ANOVA. Where a significant (P < 0.05) difference was found, we applied a Student-Newman-Keuls test to determine which comparisons were significant. Increases in MAC for a given anesthetic produced by successively faster infusion rates of strychnine were tested for significance using Student’s t test.

	Results

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MAC for cyclopropane during the infusion of aCSF was 0.185 ± 0.018 atm (zero of four rats died during the infusion of 3 µg/min of strychnine; two of six died during the infusion of 12 µg/min; and three of eight died during the infusion of 24 µg/min; data for dying rats not included). MAC for isoflurane during the infusion of aCSF was 0.0121 ± 0.0012 atm (n = 15; two of six rats died during the infusion of 12 µg/min of strychnine and three of six died during the infusion of 48 µg/kg; data for dying rats are not included). MAC for halothane during the infusion of aCSF was 0.0100 ± 0.0011 atm (no deaths during strychnine infusion). MAC increased for all anesthetics during the infusion of strychnine (Table 1; Fig. 2). At an infusion rate of 3 µg/min of strychnine, the increase in MAC was less for cyclopropane than that for either of the other two anesthetics, but an ANOVA did not reveal a significant difference between isoflurane and halothane. At infusions of 12 or 24 µg/min, the increase in MAC was less for cyclopropane than that for either of the other two anesthetics, but the increases for isoflurane and halothane did not differ.

View larger version (18K): [in this window] [in a new window]   Figure 2. Intrathecal infusion of strychnine significantly increased the minimum alveolar anesthetic concentration (MAC) of cyclopropane, isoflurane, and halothane more for the latter two than for cyclopropane. The increases in isoflurane and halothane MAC at an infusion rate of 3 µg/min of strychnine were less than the increases at the faster infusion rates. There was no significant difference in the increases in MAC at 12 and 24 µg/min for either isoflurane or for halothane. Data are displayed as mean ± SD.

View larger version (25K): [in this window] [in a new window]   Figure 3. The intrathecal infusion of 12 and 24 µg/min of strychnine increased minimum alveolar anesthetic concentration (MAC) for cyclopropane, isoflurane, and halothane in proportion to the potentiation produced in vitro by these anesthetics on glycine receptors expressed in Xenopus oocytes.

	Discussion

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Are the effects of strychnine on the MAC of cyclopropane, isoflurane, and halothane large or small? To estimate this, the effects can be compared with those seen with drug treatments or genetic modifications of another inhibitory ligand-gated chloride channel considered important to anesthetic action, the -aminobutyric acid (GABA)A receptor.

Conceptually, a maximal dose of receptor antagonist and a gene knockout should produce the same effect. The MAC of isoflurane is increased approximately 40%–50% when GABAA receptors are antagonized by spinal application of picrotoxin (14). At most, genetic modifications of the GABAA receptor have produced a 26% increase in MAC (for enflurane) with knockout of the ß3 subunit (17). However, this effect was attributable to compensation for absence of the ß3 subunit and not absence of the subunit itself (18). Other knockouts of the GABAA receptor have produced smaller effects.

The present studies have therefore shown a larger effect on the glycine receptor than have been reported with the GABAA receptor. Based on our results, we would predict that were it possible to knock out the glycine receptor, approximately an 80% increase in halothane MAC, a 65% increase in isoflurane MAC, and a 21% increase in cyclopropane MAC would be observed. These are, in fact, larger than the reported effects on MAC of any anesthetic by any receptor antagonist or genetic modification of any receptor. By these criteria, the effect we observed on MAC by antagonizing the glycine receptor is large. Furthermore, it is plausible that glycine receptors mediate part of the action of inhaled anesthetics that act via a spinal mechanism because unlike other candidate receptors for anesthetic action, glycine receptors are predominantly located in the spinal cord.

A further, simplistic calculation can be made of the extent of mediation. Consider that an increase of MAC of 100% (a doubling) indicates that half of the target receptor (in this case glycine) mediates immobility. If the target receptor mediated all of the capacity to produce immobility, the increase in MAC produced by complete antagonism of the receptor would be infinite. That is:

equation

This calculation indicates that the 79.7% increase in halothane MAC reflects a mediation of 44% of the halothane MAC by glycine receptors. For isoflurane with a 65.5% increase, the calculated mediation is 40%. For cyclopropane with a 21.7% increase, the mediation is 18%.

Such calculations assume that the measured increases in MAC result from complete blockade of the target receptor and that the increased anesthetic concentration proportionately increases the anesthetic effect of the remaining mediating receptors. We believe that complete blockade was achieved because increasing the dose of strychnine did not produce further increases in MAC of any of the anesthetics (Table 1; Fig. 2).

Despite the size of the effects seen, glycine receptors cannot be the only mediator of MAC in this study. If they were the only mediator, then there should have been a much larger increase in MAC. MAC should have increased until the rats died or the approximately 3 MAC of anesthetic that is required to immobilize a rat from a supraspinal action was achieved.

A trend suggests that the capacity of an anesthetic to potentiate the action of glycine determines the lethality of strychnine. Deaths seemed to be more frequent for the same doses of strychnine with cyclopropane (five deaths in 18 rats) than with halothane (0 deaths in 12 rats) (P = 0.12 by Fisher’s exact test, two-tailed). Such observations further support the notion of a differential effect of the anesthetics in vivo that is proportional to their in vitro receptor effects.

The findings and estimations made above suggest that glycine receptors mediate a portion of the immobility produced by inhaled anesthetics but that the mediation does not account for the majority of the capacity of anesthetics to produce immobility. Other reports indicate that the remaining effect is not mediated by acetylcholine receptors (19,20) or 5-hydroxytryptamine-3 receptors (21). Similarly, GABAA receptors may not be mediators (14). Several other receptors, including those that mediate the effects of glutamate, remain as possible candidates. The findings in the present study suggest one approach to determine the relevance of the remaining receptors. They must contribute a larger portion of the anesthetic effect in vivo of drugs that have a large in vitro effect on the receptor.

We conclude with an observation on the power of the present approach to a test of the relevance of a specific receptor as a mediator of a particular anesthetic effect. Taken alone, our data would only suggest that a particular receptor antagonist (i.e., strychnine) differentially affects anesthetic requirement. This would prove little regarding relevance other than the receptor is in the neural circuitry influencing anesthetic requirement. However, in the context of the in vitro data showing a parallel effect on the isolated glycine receptor(Fig.3), our in vivo data argue strongly for a relevant effect of glycine receptors as mediators of a portion of the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation.

	Acknowledgments

 
Supported, in part, by National Institutes of Health Grant 1P01GM47818.

	Footnotes

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

	References

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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