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Anesth Analg 2003;97:424-429 © 2003 International Anesthesia Research Society
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-Aminobutyric Acid-A and Excitatory Amino Acid Receptors
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Abstract |
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To elucidate the role of
-aminobutyric acid (GABA)A receptor complex and excitatory amino acid receptors (N-methyl-D-aspartate [NMDA] and non-NMDA receptors) in propofol-induced anesthesia, we examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol anesthesia in mice. All drugs were administered intraperitoneally. General anesthetic potencies were evaluated using a righting reflex assay. The GABAA receptor agonist muscimol potentiated propofol (140 mg/kg; 50% effective dose for loss of righting reflex) induced anesthesia. Similarly, the benzodiazepine receptor agonist diazepam and the NMDA receptor antagonist MK-801 augmented propofol anesthesia, but the non-NMDA receptor antagonist CNQX did not. In contrast, the GABAA receptor antagonist bicuculline antagonized propofol (200 mg/kg; 95% effective dose for loss of righting reflex) induced anesthesia. However, neither the benzodiazepine receptor antagonist flumazenil, the GABA synthesis inhibitor L-allylglycine, nor the NMDA receptor agonist NMDA reversed propofol anesthesia. Conversely, the non-NMDA receptor agonist kainate enhanced propofol anesthesia. These results suggest that propofol-induced anesthesia is mediated, at least in part, by both GABAA and excitatory amino acid receptors. IMPLICATIONS: We examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol-induced anesthesia in mice. The results suggest that propofol anesthesia is mediated, at least in part, by both GABAA and excitatory amino acid receptors.
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Introduction |
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General anesthetic action can be induced by enhancing inhibitory neurotransmission, by inhibiting excitatory neurotransmission, or by a combination of both, although the precise mechanism underlying anesthetic action is not fully understood. In the mammalian central nervous system (CNS),
-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and glutamate is the predominant excitatory amino acid neurotransmitter acting on N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Propofol enhances GABAergic neurotransmission mediated by the GABAA receptor complex in biochemical, electrophysiologic, and molecular biological studies (1–3). In a behavioral study, we previously reported that the GABAA receptor agonist muscimol reduced, and the antagonist bicuculline increased, the 50% effective dose (ED50) of propofol for loss of the righting reflex (4). In this study, we further examined the effects of a benzodiazepine receptor agonist and antagonist, and a GABA synthesis inhibitor on propofol-induced anesthesia in mice. In addition, propofol inhibits glutamate-mediated excitatory neurotransmission using neurochemical and electrophysiologic techniques (5–7). Therefore, we also investigated in vivo the effects of agonists and antagonists of excitatory amino acid receptors on propofol anesthesia.
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Methods |
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All experiments were approved by the Committee of Research Facilities for Laboratory Animal Science, Hiroshima University School of Medicine. Adult male ddY mice weighing 34–57 g were used for the study. Animals were housed 5 per cage in a room maintained at 23° ± 1°C with an alternating 12-h light/dark cycle. Food and water were available ad libitum. Animals were used only once in all experiments.
Propofol was prepared in 10% intralipid as an emulsion. Muscimol, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-imine (MK-801), 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), L-allylglycine, NMDA, and kainate were dissolved in 0.9% saline solution. (+)-Bicuculline was dissolved in a few drops of 0.1 N HCl, diluted with distilled water, and adjusted to approximately pH 3.0 to stabilize its effects. Diazepam and flumazenil were suspended in 1.0% carboxymethyl cellulose sodium salt solution. Each drug was freshly prepared on the day of the experiment. All drugs were administered intraperitoneally (i.p.) in a volume of 5 mL/kg.
Intraperitoneal injection of muscimol or diazepam requires 30 min to reach the peak anticonvulsant effect and this effect persists for >1 h (8,9). Simultaneous injection of flumazenil prevents the anticonvulsant effect of diazepam (9). Systemic administration of MK-801 produces impairment of the righting reflex. The peak effect occurs 30 min after the i.p. injection and this effect continues for >1 h (10). In a global ischemia model, i.p. injection of CNQX prevents neuronal cell death in the hippocampus, but the duration of its action is approximately 30 min (11). In a previous study, propofol anesthesia peaked 6 min after i.p. administration (4). Therefore, muscimol, diazepam, flumazenil, and MK-801 were administered 30 min before the administration of propofol. CNQX was injected simultaneously with propofol. Bicuculline, NMDA, and kainate were given simultaneously with propofol, because we confirmed in preliminary studies that convulsions induced by these drugs occur within 10 min after injection. The effects of bicuculline, NMDA, and kainate on the anesthetic potencies induced by propofol were compared at the ED50 for inducing convulsions. We used the ED50 of 5.0 (4.1–6.2; 95% confidence limits) mg/kg for bicuculline, 145 (124–170) mg/kg for NMDA, and 23 (19–29) mg/kg for kainate. In a previous study, 200 mg/kg L-allylglycine, a GABA synthesis inhibitor, induced convulsions approximately 90 min after injection (12). A similar dose of L-allylglycine produces a significant decrease in the GABA level at 30 min after the injection, progressing to an approximately 40% decrease at 60 min, but no further substantial change at 2 h (13,14). Therefore, 200 mg/kg L-allylglycine was administered 60 min before propofol. In a previous study, the i.p. administration of propofol increased the percentage of loss of the righting reflex in a dose-dependent manner with an ED50 value of 140 (123–160) mg/kg (4). Therefore, a dose of 140 mg/kg (ED50) was used when the effect of muscimol, diazepam, MK-801, or CNQX was examined. At larger doses of propofol (175–200 mg/kg), >80% of the mice showed loss of the righting reflex (4). Thus, a dose of 200 mg/kg (ED95) was used when the effect of bicuculline, flumazenil, L-allylglycine, NMDA, or kainate was investigated. The anesthetized animals were kept warm with an overhead heat lamp.
The mice were examined individually in a circular glass beaker (13.5-cm diameter x 19-cm high). After the administration of propofol, we tilted the beaker by hand to an angle of approximately 45° with a horizontal plane in triplicate at each recording time. Righting reflex was assessed and recorded every 2 min after injection for a maximum of 2 h by a blinded observer. Anesthetic scores were evaluated according to the rating scale (15): a score of 0 indicated a normal righting reflex; +1 indicated that the mouse righted itself within 2 s on all 3 trials (slightly impaired righting reflex); +2 indicated that the latency to righting was >2 s, but <10 s at the best response in 3 trials (moderately or severely impaired righting reflex); +3 corresponded to the absence of this reflex (no righting within 10 s on all 3 trials).
Total anesthetic scores were the total of the scores recorded every 2 min after the propofol injection for a maximum of 2 h. Animals were considered to have lost their righting reflex when they scored +3. The time between the loss of the ability to right themselves (shown as a score of +3) and the time they regained that ability (shown as a score of +2) was considered the duration of loss of the righting reflex (minutes). The time required to return to a normal righting reflex (shown as a score of 0) was considered the recovery time (minutes).
Data for total anesthetic scores were represented as median ± range, and were analyzed by Kruskal-Wallis one-way analysis of variance (ANOVA), followed by Dunn’s test for multiple comparisons. Data for duration of loss of righting reflex and recovery time were represented as mean ± SEM, and were analyzed by one-way ANOVA, followed by Student’s t-test with Bonferroni correction for multiple comparisons. The results were considered statistically significant when P < 0.05.
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Results |
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The GABAA receptor agonist muscimol at doses of 0.4–1.0 mg/kg, which did not on their own produce any impairment of the righting reflex, significantly increased the total anesthetic scores (H = 10.151, P = 0.0012; Kruskal-Wallis one-way ANOVA), the duration of loss of the righting reflex (F[3,28] = 6.985, P = 0.0012; one-way ANOVA), and the recovery time (F[3,28] = 6.995, P = 0.0012) induced by 140 mg/kg propofol. Similarly, diazepam (1–3 mg/kg), a benzodiazepine receptor agonist, and MK-801 (0.05–0.20 mg/kg), an NMDA receptor antagonist, dose-dependently augmented the impairment of the righting reflex (H = 14.991, P = 0.0006 and H = 14.471, P = 0.0023, respectively), the duration of loss of the righting reflex (F[2,27] = 14.767, P < 0.0001 and F[3,30] = 7.656, P = 0.0006, respectively), and the recovery time (F[2,27] = 15.179, P < 0.0001 and F[3,30] = 12.222, P < 0.0001, respectively) induced by 140 mg/kg propofol. In contrast, a sufficiently neuroprotective dose of CNQX (60 mg/kg), a non-NMDA receptor antagonist, did not affect the general anesthetic potencies induced by propofol 140 mg/kg (P > 0.05) (Table 1).
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The GABAA receptor antagonist bicuculline at doses of 2–5 mg/kg significantly decreased total anesthetic scores (H = 17.782, P = 0.0005), the duration of loss of the righting reflex (F[3,30] = 9.160, P = 0.0002), and the recovery time (F[3,30] = 9.947, P = 0.0001) induced by 200 mg/kg propofol in a dose-dependent manner. In contrast, neither the benzodiazepine receptor antagonist, flumazenil (2–20 mg/kg), nor the GABA synthesis inhibitor, L-allylglycine (200 mg/kg), reversed anesthesia induced by 200 mg/kg propofol (P > 0.05). No convulsions were found in bicuculline-propofol- and L-allylglycine-propofol-treated mice during the test period. Because the NMDA receptor agonist NMDA at ED50 (145 mg/kg) for inducing convulsions produced seizures and death even in mice treated with a large anesthetic dose of propofol (200 mg/kg), we used ED25 (120 mg/kg) and ED5 (100 mg/kg) for NMDA. These doses did not affect the general anesthetic potencies induced by 200 mg/kg propofol (P > 0.05). In contrast, the non-NMDA receptor agonist, kainate (23 mg/kg), significantly enhanced the propofol-induced anesthesia (P < 0.05) (Table 2).
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Discussion |
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The present study showed that the GABAA receptor agonist muscimol potentiated propofol-induced anesthesia. Similarly, the benzodiazepine receptor agonist diazepam and the NMDA receptor antagonist MK-801 augmented propofol anesthesia, but the non-NMDA receptor antagonist CNQX did not (Table 1). In contrast, the GABAA receptor antagonist, bicuculline, antagonized propofol anesthesia. However, neither the benzodiazepine receptor antagonist, flumazenil, the GABA synthesis inhibitor, L-allylglycine, nor the NMDA receptor agonist, NMDA, reversed propofol anesthesia. Conversely, the non-NMDA receptor agonist, kainate, enhanced propofol anesthesia (Table 2). These results suggest that propofol-induced anesthesia may both activate the postsynaptic GABAA receptors independently of the benzodiazepine receptors and inhibit the excitatory amino acid receptors.
Diazepam enhanced propofol-induced anesthesia (Table 1). Diazepam acts via the benzodiazepine binding site on the GABAA receptor (16), whereas propofol may interact with the benzodiazepine receptor via another binding site. In fact, flumazenil did not antagonize propofol anesthesia (Table 2). Furthermore, because diazepam is a sedative-hypnotic drug that causes loss of the righting reflex on its own, any potentiation by diazepam of the anesthetic action of propofol may not be construed per se as evidence that both drugs act on the same receptor. Benzodiazepines are likely to potentiate the actions of any drug causing loss of the righting reflex, even when that drug has no activity at the GABAA receptor. Therefore, the effect of propofol on loss of the righting reflex may be independent of benzodiazepine receptor activation.
Systemic administration of muscimol induces depressant effects, such as impairment of motor coordination and sedation, especially in large doses (17). There is a possibility, therefore, that additive effects between muscimol and propofol may occur via action at different sites. Moreover, bicuculline may antagonize the depressant action of propofol regardless of its site of action because bicuculline is a potent neuroexcitant and convulsant. If propofol did not enhance the inhibitory neurotransmission mediated by GABAA receptors, it would not prevent convulsions induced by bicuculline. It has been reported that propofol suppresses convulsions induced by bicuculline and picrotoxin, a noncompetitive GABAA receptor antagonist (18). Similarly, in this study, mice treated with propofol-bicuculline (5 mg/kg; ED50 for convulsions) and propofol-L-allylglycine (200 mg/kg; a large, convulsive dose) showed no convulsions during the test period (data not shown). In addition, bicuculline reversed propofol-induced anesthesia in a dose-dependent manner (Table 2). These findings suggest that the effects of these GABAA receptor ligands on propofol anesthesia occur via their specific sites of action. Thus, propofol seems to produce anesthesia through an enhancement of GABAA receptor-mediated neurotransmission, but not through a nonspecific action.
L-Allylglycine at a dose of 200 mg/kg induces seizures, suggesting that this dose reduces GABA in presynaptic nerve terminals to a point lower than the level required physiologically in the brain. However, this dose of L-allylglycine did not affect propofol-induced anesthesia (Table 2). This finding indicates that propofol’s potentiation of GABAergic neurotransmission is not presynaptic or is not caused by indirect effects mediated through neuronal networks. In fact, an electrophysiologic study has revealed that propofol directly activates the postsynaptic GABAA receptor in the hippocampus of rats (2).
In this study, NMDA was administered i.p. Moreau et al. (19) have shown that neurologic and behavioral changes induced by systemic administration of NMDA are not very reproducible, whereas changes induced by intracerebroventricular (i.c.v.) injection of NMDA are reproducible. However, many tests on convulsions, learning, and memory have been performed using i.p. injection of NMDA (20–22). Intraperitoneal administration of NMDA dose-dependently produces a variety of behavioral changes (23), whereas i.c.v. injection of a very small dose (1 nmol in 1 µL) yields convulsions in <1 minute (19). Furthermore, it has been reported that in learning and memory tests, even smaller doses of NMDA (10–50 mg/kg, i.p.) are sufficiently effective (22). Therefore, we used i.p. administration, and not i.c.v. injection technique.
The systemic administration of kainate resulted in the potentiation of propofol-induced anesthesia in mice, suggesting that kainate may act agonistically at the GABAA receptors and/or antagonistically at the excitatory amino acid receptors in the CNS. This speculation is supported by reports that systemic administration of kainate increases extracellular GABA levels in the hippocampus of rats measured by brain microdialysis (24,25). Moreover, kainate antagonizes myoclonic seizures and the increase in muscle tone produced by NMDA, and potentiates both the anticonvulsant and myorelaxant actions of 2-amino-7-phosphonoheptanoate (AP-7), a competitive NMDA receptor antagonist (26). Peptides derived from kainate also antagonize the response to NMDA in vitro (27). However, the precise nature of the mechanism is uncertain.
It has been shown in biochemical studies that a small concentration of propofol (10 µM) produces a marked increase in the affinity of [3H]GABA binding to rat cortical membrane preparations and potentiates muscimol-induced stimulation of 36C- uptake in membrane vesicle preparations (1). An electrophysiologic study has demonstrated that propofol at clinically relevant concentrations (10–20 µM) directly activates the GABAA receptor-chloride ionophore complex in dissociated hippocampal pyramidal neurons of rats (2). Molecular biological and electrophysiologic evidence has also revealed that propofol (15 µM) enhances GABA-induced Cl- currents elicited on GABAA receptors expressed by Xenopus oocytes (3). These in vitro findings suggest that postsynaptic GABAA receptors are important sites for propofol action.
Glutamate is the major excitatory amino acid neurotransmitter in the CNS. Glutamatergic neurons and synapses are distributed widely throughout the CNS, but they are concentrated particularly in the hippocampus, the outer layers of the cerebral cortex, and the substantia gelatinosa of the spinal cord. Within these regions, the excitatory amino acid has the key role in physiologic processes, including learning and memory (and hence awareness under anesthesia), and central pain transduction mechanisms (28). It has been shown that large concentrations of propofol (100 µM to 1 mM) produce a reversible, dose-dependent inhibition of whole cell currents activated by NMDA, but not kainate, in cultured hippocampal neurons of mice (5). Large concentrations of propofol (500 µM to 1 mM) suppress the current responses of the AMPA-, kainate-, and NMDA-selective receptor channels expressed in Xenopus oocytes. A clinical concentration (20 µM) slightly suppresses the NMDA receptor channels alone (6). These electrophysiologic studies indicate that the effects of propofol on glutamate receptors require considerably larger concentrations than those on GABAA receptors. In contrast, a neurochemical study has shown that a small concentration of propofol (10 µM) inhibits K+-evoked glutamate release from rat cerebrocortical slices, although the inhibition by propofol is mediated by activation of GABAA receptors (7). In the present behavioral study, small doses of MK-801, which did not on their own produce any impairment of the righting reflex, potentiated propofol anesthesia in a dose-dependent manner (Table 1). These in vitro and our in vivo findings suggest that propofol-induced anesthesia may involve an inhibition of excitatory amino acid receptor-mediated neurotransmission.
In conclusion, propofol-induced anesthesia is mediated, at least in part, by both GABAA and excitatory amino acid receptors, although the former seems to have a more important role in the anesthetic action of propofol than the latter.
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Acknowledgments |
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This work was supported in part by Grant-in-Aid 13672097 for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture of Japan.
We thank Mr. Steven L. Leeper, Transnet, Inc., and Dr. Sarah Salvage, King’s College London, for English language editing. We also acknowledge Yamanouchi Pharmaceutical Co. for donation of flumazenil.
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