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Department of Anesthesia and Perioperative Care, University of California, San Francisco
Address correspondence and reprint requests to James M. Sonner, MD, Department of Anesthesiology and Perioperative Care, Room S-455I, Box 0464, 513 Parnassus Ave., University of California, San Francisco, CA 94143-0464. Address e-mail to sonnerj{at}anesthesia.ucsf.edu
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Abstract |
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-amino-n-butyric acid subtype A (GABAA) receptors purportedly underlies its anesthetic effects. However, a recent study found that a GABAA antagonist did not alter the capacity of propofol to depress the righting reflex. We examined whether the noncompetitive GABAA antagonist picrotoxin and the competitive GABAA antagonist gabazine affected a different anesthetic response, immobility in response to a noxious stimulus (a tail clamp in rats), produced by propofol. This effect was compared with that seen with ketamine and isoflurane. Picrotoxin increased the 50% effective dose (ED50) for propofol by approximately 379%; gabazine increased it by 362%, and both antagonists acted in a dose-related manner with no apparent ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED50 for ketamine by approximately 40%–50%, whereas gabazine increased it by 50%–60%. The isoflurane minimum alveolar anesthetic concentration increased by approximately 60% with the picrotoxin and 70% with the gabazine infusion. The ED50 for propofol was also antagonized by strychnine, a non-GABAergic glycine receptor antagonist and convulsant, to determine whether excitation of the central nervous system by a non-GABAergic mechanism could account for the increases in propofol ED50 observed. Because strychnine only increased the immobilizing ED50 of propofol by approximately 50%, GABAA receptor antagonism accounted for the results seen with picrotoxin and gabazine. We conclude that GABAA antagonism can influence the ED50 for immobility of propofol and the non-GABAergic anesthetic ketamine, although to a different degree, reflecting physiologic antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the neural circuitry underlying immobility) versus physiologic and pharmacologic antagonism for propofol (i.e., a direct effect by antagonism of propofol’s mechanism of action). This study also suggests that the immobilizing action of isoflurane probably does not involve the GABAA receptor because antagonism of GABAA receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol.
IMPLICATIONS: IV picrotoxin and gabazine antagonized the immobilizing action of propofol in a dose-related manner, whereas antagonism of the immobilizing action of ketamine and isoflurane was similar, smaller than for propofol, and not dose-related. These results are consistent with a role for -amino-n-butyric acid subtype A receptors in mediating propofol anesthesia but not ketamine or isoflurane anesthesia.
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Introduction |
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-amino-n-butyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. In response to binding of GABA, GABA type A (GABAA) receptors open to allow passage of chloride through the channel. The cell is thus hyperpolarized and excitability reduced. Many anesthetics enhance the action of GABA at GABAA receptors in vitro. Propofol strongly enhances such action (1,2), and this enhancement may underlie its anesthetic effect. However, sparse evidence in animals supports such a suggestion. If GABAA receptors mediate the anesthetic actions of propofol, then animals given a GABAA receptor antagonist should require more anesthetic. However, Little et al. (3) reported that administration of the GABAA receptor antagonist bicuculline to mice did not increase propofol requirements as defined by the loss of righting reflex. This finding calls into question the importance of GABAA receptors to the in vivo anesthetizing action of propofol.
Accordingly, we studied the effect of GABAA receptor blockade on immobility produced by the (presumably) GABAergic anesthetic propofol and compared this effect with that of GABAA receptor blockade on anesthesia produced by a non-GABAergic anesthetic, ketamine. Ketamine is thought to act primarily by noncompetitive blockade of N-methyl-D-aspartate receptors (4) and does not significantly affect GABAA receptors at clinical concentrations. Ketamine does antagonize nicotinic receptors (5), but antagonism of these receptors does not influence the minimum alveolar anesthetic concentration (MAC) (6). We further studied the effect of GABAA blockade on isoflurane and compared the result to the benchmarks seen with propofol and ketamine.
Our experimental design differed from that constructed by Little et al (3). We used picrotoxin and gabazine, and we studied the effect of these antagonists on immobility in response to a noxious stimulus in rats. Picrotoxin blocks the chloride channel pore of GABAA receptors (7). In neonatal animals (which were not used in this study), it also blocks homomeric glycine 
receptors (8). Gabazine is a competitive GABAA receptor antagonist. We used these drugs in most of our studies rather than bicuculline, which is also a competitive GABAA antagonist, because bicuculline (free base) is only sparingly soluble in aqueous solution, whereas the often-used N-methyl salts of bicuculline are not specific for GABAA receptors (9). We chose immobility in response to noxious stimuli as our anesthetic end-point because we are interested in clinical anesthesia, i.e., the response of animals to painful stimuli. We chose rats rather than mice because we inserted catheters to infuse drugs and thereby approach a steady-state effect in our animals, and the larger size of rats facilitated such insertion.
We first studied the capacity of picrotoxin and gabazine administered IV to antagonize the immobilizing action of propofol and (separately) ketamine, also administered IV, and of isoflurane administered by inhalation. We hypothesized that the 50% effective dose (ED50) of propofol would be antagonized more than that of ketamine by virtue of the effect of propofol on GABAA receptors and the absence of that effect for ketamine. We compared the antagonism of isoflurane’s immobilizing action with that seen with ketamine and propofol to determine whether isoflurane was GABAergic or non-GABAergic in its immobilizing action.
As a control, in a subsequent experiment, we assessed the effect of excitation of the nervous system from strychnine (a glycine receptor antagonist and convulsant) on the ED50 of propofol. If the results of antagonizing the ED50 of propofol with either picrotoxin or gabazine were simply because of excitation of the nervous system rather than specific effects on the GABAA receptor, then strychnine should produce similar results.
In a limited number of experiments, we also followed Little et al.’s (3) protocol to determine whether there was a change in the MAC of isoflurane with intraperitoneal (ip) injection of bicuculline.
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Methods |
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The ED50 at which rats moved in response to a tail clamp for propofol and (separately) for ketamine given IV was determined and then redetermined in the same rat in which study drug was co-administered with picrotoxin or gabazine IV. Propofol’s ED50 was also determined in rats receiving strychnine.
Picrotoxin doses ranging from 4.8 µg/min to 153.6 µg/min were used. Rats died when ketamine and picrotoxin were administered concurrently at doses larger than 19.2 µg/min. Thus, in separate studies, a constant dose of the inhaled anesthetic isoflurane (0.38% atm [0.25 MAC] in one study and 0.75% atm [0.5 MAC] in another) was given while determining the infusion rate of ketamine and propofol (in micrograms per minute IV) that prevented movement in 50% of rats (ED50). The increases for rats given ketamine were compared with those given propofol in rats inhaling the same concentrations of isoflurane.
Gabazine in doses of 5 to 1280 µg/min was used. Doses larger than 1280, 320, and 640 µg/min could not be studied because they were lethal to rats anesthetized with propofol, ketamine, and isoflurane, respectively. Isoflurane was not co-administered in studies with gabazine.
Strychnine doses of 8 to 128 µg/min were studied. Doses larger than 64 µg/min could not be studied in rats receiving only propofol because they were lethal, whereas doses larger than 128 µg/min were lethal to rats receiving propofol with 0.75% isoflurane.
The ED50 values for IV propofol and ketamine were determined using a bracketing approach similar to that used for the determination of isoflurane MAC. Four rats were studied at a time. Because the concurrent administration of isoflurane decreased the ED50 for propofol and ketamine, smaller starting infusions of those drugs were used when isoflurane was co-administered. Using 0.38% isoflurane, the starting infusion rate for propofol was 450 µg · kg-1 · min-1, whereas for ketamine, the starting infusion rate was 1200 µg · kg-1 · min-1. Using 0.75% isoflurane, the starting infusion rate of propofol was 250 µg · kg-1 · min-1 and for ketamine was 600 µg · kg-1 · min-1. When propofol was administered IV with picrotoxin in the absence of isoflurane, the starting infusion rate varied between 600 and 900 µg · kg-1 · min-1. For the studies with gabazine, the starting doses of the anesthetics were similar to those for picrotoxin.
In all studies, after 30 min, the rats’ responses to a 1-min tail clamp were assessed. If the rats moved, the infusion rate was increased by approximately 20%. After 30 min, the tail clamp was again applied. This process was continued until the rats did not move in response to the tail clamp. The ED50 for each rat was the average of the largest dose that permitted movement and the smallest dose that prevented movement. For a given drug, the ED50 was the average of the ED50s for the individual rats.
Isoflurane MAC in rats receiving IV picrotoxin or gabazine was determined using methods previously described (10). MAC for each rat was the average of the largest concentration of isoflurane (measured by gas chromatography) at which the rat moved in response to a 1-min tail clamp and the smallest concentration at which it did not move in response to a 1-min tail clamp.
All three anesthetics used in this study (isoflurane, propofol, and ketamine) suppressed convulsions. Accordingly, the convulsive effect of the ip bicuculline was determined in rats that were not anesthetized.
Bicuculline was dissolved in normal saline. Solubility was promoted by the addition of 0.1 N of HCl. The ip dose producing convulsions and latency to convulsions was determined. Using bicuculline doses at or larger than the convulsive ED50, the effect of ip bicuculline on MAC of isoflurane was studied. MAC was determined in four to six rats and then redetermined in the same rats after bicuculline was injected. Doses from 4 to 48 mg/kg of bicuculline were administered ip. The volume injected varied from 0.67 to 6.27 mL. Bicuculline was injected 15 min before applying the tail clamp while the rats were inhaling the smallest dose of anesthetic that had prevented movement in response to a tail clamp.
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 (infective dose) 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 of hydrogen and 240 mL/min of air. Primary (volumetric) standards were prepared for isoflurane by injecting a known volume of liquid isoflurane into a gas-tight flask of known volume. The linearity of the response of the chromatograph to isoflurane was determined using dilutions made from the primary standard. We routinely also used secondary (cylinder) standards containing isoflurane, which were calibrated against the primary (volumetric) standards.
Results are reported as percentage changes in ED50 using mean and SD unless otherwise noted. A one-way analysis of variance with a post hoc Student-Newman-Keuls test was used to determine differences in ED50 among different antagonist doses for the same anesthetic. Student’s t-test was used to compare anesthetic groups at the same antagonist dose, with a Bonferroni correction for multiple comparisons. A P value, after correction for multiple comparison testing, of <0.05 was considered significant.
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Results |
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Strychnine increased the ED50 for propofol by at most 48% ± 16% (n = 3), which was achieved with an infusion of 64 µg/min (Fig. 5). Rats died when larger doses were attempted but did not convulse. The addition of isoflurane 0.75% allowed the study of one larger dose of strychnine (128 µg · kg-1 · min-1). The increase in the ED50 of propofol at that dose was 77% ± 41% (n = 4) and no different than at the previous dose of propofol (64 µg/min with 0.75% isoflurane) where a 74% ± 26% (n = 4) change was observed. Doses larger than 128 µg · kg-1 · min-1 of strychnine in the presence of propofol and 0.75% isoflurane were lethal.
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Discussion |
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To what extent does the antagonism of the anesthetic effect of propofol by GABAA antagonists reflect pharmacologic antagonism (a direct effect by antagonism of GABAA receptors on which propofol acts) as opposed to physiologic antagonism (an indirect effect that would be observed with non-GABAergic anesthetics) (11)? To answer this question, we evaluated the effect of picrotoxin and gabazine on the ED50 of ketamine, an anesthetic that does not act on GABAA receptors in vitro, at clinically relevant doses (5). As a result, any effect of picrotoxin or gabazine on the ED50 of ketamine must reflect only an indirect or modulatory effect (physiologic antagonism). A maximal effect on ketamine’s ED50 was seen at small doses of picrotoxin compared with propofol. We conjecture the reason is that the excitatory effects of GABAA receptor blockade were unopposed by ketamine but counterbalanced by propofol. To study ketamine and picrotoxin at doses used to antagonize propofol anesthesia, we allowed rats to inhale isoflurane at 0.25 MAC and in a separate study at 0.5 MAC. The addition of the isoflurane permitted survival at larger doses of picrotoxin. Under these conditions, picrotoxin increased the ED50 of ketamine by 54% to 86%. By contrast, under the same conditions, the ED50 of propofol increased 416% to 440% (significantly different from the result with ketamine.)
These results are consistent with an antagonism of a tonic output of GABA by ketamine (physiologic antagonism) (11). The results for propofol are consistent with antagonism of that tonic output plus an antagonism of the enhancement of that output by propofol (physiologic plus pharmacologic antagonism). This latter result would be predicted from the large in vitro enhancing action of propofol on GABAA receptors.
The results of using gabazine to antagonize the immobilizing ED50 of propofol and ketamine supported the results obtained with picrotoxin. A 54% increase, at most, in ketamine ED50 was measured compared with a 362% increase for propofol.
The ED50 increase for ketamine antagonized by either picrotoxin or gabazine is remarkably similar to the MAC increases for isoflurane antagonized by picrotoxin (12) or gabazine. Picrotoxin 76.8 µg/min IV increased isoflurane MAC by approximately 63% (Fig. 1). Isoflurane MAC increased by 74% when gabazine was given, an amount not significantly different from that obtained with picrotoxin. The similar percentage increases with ketamine and isoflurane contrast with the far larger increases in ED50 observed with propofol. The similarity between ketamine and isoflurane suggests that GABAA receptors are as important to the immobilizing action of isoflurane as they are for ketamine. That is, GABAA receptors have an indirect or modulatory effect on immobility that can be observed when an antagonist is given in a sufficient dose, but the direct effect of isoflurane on GABAA receptors is by itself of little importance to the immobilizing action of isoflurane.
That the large changes in ED50 of propofol were not the result of central nervous system excitation independent of GABAA antagonism was demonstrated by infusing strychnine up to lethal doses and measuring the effect on the ED50 of propofol. The faster infusion rate of strychnine that was not lethal increased the ED50 of propofol by just less than 50%. Thus, central nervous system excitation in the absence of GABAA antagonism cannot explain the much larger increases in the ED50 of propofol seen with gabazine or picrotoxin infusion. These results also suggest that glycine potentiation is not of great importance to the immobilizing action of propofol.
Our results differ from those of Little et al. (3) in that we found antagonism of propofol anesthesia by GABAA receptor antagonists. However, when we followed their protocol to choose a dose of bicuculline and injected that dose ip, we observed no change in isoflurane MAC. The dose of bicuculline used in that experiment was at approximately the convulsive ED50. As shown in Figure 6, antagonism of isoflurane MAC by ip bicuculline requires approximately 10 times the convulsive ED50 dose of bicuculline. Similarly, with our protocol for picrotoxin and gabazine, we used successively larger infusions of picrotoxin and gabazine, and in doing this, we performed a full dose-response study from no effect to lethal doses of receptor antagonist. Thus, a greater degree of receptor antagonism was likely achieved in our studies, which may account for the pronounced antagonism of propofol’s immobilizing ED50 that we observed and the lack of antagonism observed in Little et al.’s study. Other differences in experimental design may also account for the finding of antagonism in one study and not the other. We studied immobility in response to a noxious stimulus rather than righting reflex. The neural mechanisms underlying these behaviors may differ and accordingly be differently affected. We used infusions to obtain (or at least approach) steady-state conditions rather than ip boluses of bicuculline. Finally, we used rats rather than mice.
Our results confirm, in rats, the major contribution of GABAA receptors to the immobilizing action of propofol. These studies also confirm the validity of using antagonists in investigations of anesthetic mechanisms in animals. An antagonist to a receptor that is important to anesthetic-induced immobility should change the ED50 for immobility by a different amount and in a qualitatively different fashion (no plateau effect versus a plateau effect) for an anesthetic that acts on that receptor (e.g., propofol in the current study of GABAA receptors) compared with an anesthetic that does not (e.g., ketamine in this study). Indeed, studies parallel to these examining the role of GABAA receptors to the action of volatile anesthetics are feasible because volatile anesthetics devoid of effect of GABAA receptors are available (e.g., xenon (13) and cyclopropane (14)) that can serve the role that ketamine played in the current studies.
Finally, we found that both picrotoxin and gabazine antagonized the immobilizing ED50 (MAC) of isoflurane by an amount similar to that of ketamine. That is, isoflurane acted like a non-GABAergic anesthetic to immobility. From this, we conclude that notwithstanding the enhancing action of isoflurane on GABAA receptors observed in vitro, the immobilizing action of isoflurane probably does not involve GABAA receptors to a significant extent in vivo.
In summary, we demonstrated that the GABAA antagonists picrotoxin and gabazine antagonized the immobilizing effect of propofol, an anesthetic that significantly enhances the effect of GABA on GABAA receptors in vitro. The maximal effect of this antagonism was three to four times greater than that found with ketamine, an anesthetic that does not enhance the effect of GABA in vitro, and unlike ketamine, it did not reach a plateau. These results are consistent with the notion that propofol produces anesthesia in vivo, defined as suppression of movement evoked by noxious stimuli in part or whole by acting on GABAA receptors. We interpret the smaller increase seen with ketamine, which reaches a plateau, as consequent to physiologic antagonism of the effect of normal tonic output of GABA. The present study also suggests that the immobilizing action of isoflurane probably does not involve the GABAA receptor because antagonism of GABAA receptors for animals anesthetized with isoflurane produces results quantitatively and qualitatively similar to ketamine and markedly different from propofol.
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Acknowledgments |
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The authors would like to thank Professors R. Adron Harris and E.I. Eger for their many suggestions in regard to these studies.
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Footnotes |
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