BJA Advance Access originally published online on September 13, 2006
British Journal of Anaesthesia 2006 97(5):687-694; doi:10.1093/bja/ael239
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Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats
Experimental Anaesthesiology Section, Department of Anaesthesiology University of Tuebingen, Tuebingen, Germany
*Corresponding author: Experimental Anaesthesiology Section, Department of Anaesthesiology and Intensive Care, Eberhard Karls University, Schaffhausenstrasse 113, D-72072 Tuebingen, Germany. E-mail: christian.grasshoff{at}uni-tuebingen.de
Accepted for publication June 19, 2006.
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Abstract |
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Background. Volatile anaesthetics are widely used agents in clinical anaesthesia, although their mechanism of action is poorly understood. In particular, the dominant molecular mechanisms by which volatile anaesthetics depress spinal neurones and thereby mediate spinal effects such as immobility have recently become a matter of dispute. As GABAA and glycine receptors are potential candidates we investigated the impact of both receptor systems in mediating the depressant effects of isoflurane and enflurane on spinal neurones in rats.
Methods. The effects of isoflurane and enflurane on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurones in cultured spinal cord tissue slices obtained from embryonic rats (E 14–15).
Results. Isoflurane and enflurane reduced spontaneous action potential firing. Concentrations causing half-maximal effects (isoflurane: 0.17 mM; enflurane: 0.50 mM) were less than EC50-immobility (isoflurane: 0.32 mM; enflurane: 0.62 mM). Effects of isoflurane were mediated by 39% by glycine receptors and 36% by GABAA receptors. The effects of enflurane were mediated 26% by GABAA receptors and 29% by glycine receptors.
Conclusion. These results demonstrate that the effects of isoflurane and enflurane on GABAA and glycine receptors contribute almost equally to their depressant actions on spinal ventral horn neurones in rats. The fraction of inhibition mediated by both receptor systems differs between specific volatile anaesthetics. Our data argue against the theory that a dominant molecular mechanism accounts for spinal effects of volatile anaesthetics.
Keywords: anaesthetics volatile; molecular mechanisms; neurones, spinal
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Introduction |
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The spinal cord is an important site of anaesthetic action.1–3 There is ample evidence that anaesthetic-induced ablation of movement is predominantly mediated by depressant actions on spinal neurones.2 4 5 As glycine and GABAA receptors are expressed in the spinal cord at substantial levels, and both receptor types are potentiated by halogenated ether anaesthetics including isoflurane, enflurane and sevoflurane,2 they are likely candidates for mediating immobility.
However, in a comprehensive review, leading researchers in the field concluded recently that GABAA receptors are not involved in immobility,3 because i.v. or intrathecal application of GABAA receptor antagonists only slightly decreased the efficacy of isoflurane in depressing withdrawal reflexes in rats.6 7 This hypothesis is somewhat at variance with more recent studies on ß3 knock-in mice. These animals carry a subtle point mutation in the ß3 subunit of GABAA receptors, rendering receptors containing the mutated subunit insensitive to several anaesthetic agents.8 In these mice the EC50-immobility for isoflurane and enflurane is significantly higher compared with wild-type mice.8–10 According to the hypothesis that GABAA receptors do not contribute to immobilizing actions of volatile anaesthetics, we ask in the present study whether isoflurane and enflurane depress spinal ventral horn neurones in vitro via glycine but not via GABAA receptors. We quantified the effectiveness of both anaesthetics in depressing action potential firing in the presence and absence of GABAA and glycine receptor antagonists assuming that isoflurane and enflurane will be similarly effective in the absence and presence of selective GABAA antagonists if GABAA receptors do not contribute to their depressant effects. Furthermore, both anaesthetics will be expected to be less effective in the presence of a glycine receptor antagonist, if glycine receptors are major anaesthetic targets in the spinal cord.
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Spinal slice cultures
All procedures were approved by the animal care committee (Eberhard Karls University, Tuebingen, Germany) and were in accordance with the German law on animal experimentation. Preparation of embryonic spinal cord slices from pregnant Sprague–Dawley rats (day 14–15) was performed according to the method described by Braschler and colleagues.11 Pregnant Sprague–Dawley rats (day 14–15) were anaesthetized and decapitated and the uterus was aseptically removed into a sterile Petri dish. Embryos were placed in ice-cold Gey's balanced salt solution consisting of 1.5 mM CaCl2, 5 mM KCl, 0.22 mM KH2PO4, 11 mM MgCl2, 0.3 mM MgSO4, 137 mM NaCl, 0.7 mM NaHCO3 and 33 mM D-glucose. Spinal columns were freed from inner organs and limbs and were cut transversely into 300 µm slices using a vibratome. Afterwards, slices were placed on a coverslip and embedded in a plasma clot consisting of 20 µl heparin-treated chicken plasma and coagulated by 20 µl of a thrombin solution. The coverslips were inserted into plastic tubes containing 0.75 ml of nutrient fluid (horse serum 25 vol%, Hanks’ Balanced Salt Solution 25 vol%, Basal Medium Eagle 50 vol%, L-glutamine 1 mM, D(+)-glucose 0.05 mM; all from Sigma, Taufkirchen, Germany) including 10 nM NGF (Sigma, Taufkirchen, Germany) and incubated in an atmosphere of 95% oxygen and 5% carbon dioxide at 36.0°C for 1–2 h. The roller tube technique described by Gahwiler was used to culture the tissue.12 After 1 day in culture, antimitotics (10 µM 5-fluoro-2-deoxyuridine, 10 µM cytosine-ß-D-arabino-furanoside and 10 µM uridine) were added to reduce proliferation of glial cells. Slices were used between 12 and 35 days in vitro for extracellular recordings.
Extracellular recordings
Spinal cord slices were continuously perfused with an artificial cerebrospinal fluid (ACSF) consisting of 120 mM NaCl, 3.3 mM KCl, 1.13 mM NaH2PO4, 26 mM NaHCO3, 1.8 mM CaCl2 and 11 mM D-glucose and were bubbled with 95% oxygen and 5% carbon dioxide. Glass electrodes with a resistance of approximately 2–5 M
were filled with ACSF and were introduced into the tissue until extracellular single or multi-unit spike activity exceeding 100 µV in amplitude could be clearly identified. Ventral horn interneurones were seen by means of an Axiovert 135M inverted microscope (40x DIC, Zeiss, Göttingen, Germany).
Preparation and application of test solutions
Test solutions including isoflurane or enflurane were prepared as described previously,13 by dissolving the liquid form in ACSF equilibrated with 95% oxygen and 5% carbon dioxide. A closed, air-free system was used to prevent evaporation. Anaesthetic levels are given as multiples of minimum alveolar concentration (MAC). These MAC values refer to the plasma or blood concentrations of volatile anaesthetics in mammals at 37°C. We used the EC50 values for general anaesthesia proposed by Franks and Lieb.14 Thus we assume that 1 MAC corresponds to an aqueous concentration of 0.32 mM isoflurane and 0.62 mM enflurane.13
Anaesthetics were administered via bath perfusion using gas-tight syringe pumps (ZAK, Marktheidenfeld, Germany), which were connected to the experimental chamber via Teflon tubing (Lee, Frankfurt, Germany). The flow rate was approximately 1 ml min–1. To ensure steady-state conditions, recordings during anaesthetic treatment were carried out 10–15 min after starting the perfusate change.
Data analysis
Data were bandpass filtered between 0.5 and 1 kHz and acquired on a personal computer using the digidata 1200 AD/DA interface (Molecular Devices, Union City, CA, USA). Records were additionally stored on a Sony data recorder PC 204A (Racal Elektronik, Bergisch Gladbach, Germany). Further analysis was performed using self-written software in OriginPro version 7 (OriginLab Corporation, Northampton, MA, USA) and MATLAB 6.5 (The MathWorks Inc., Natick, MA, USA).
Data analysis was performed as previously described.15 After close inspection of the data, a threshold was set manually to detect action potentials. Mean firing rates were obtained from single- or multi-unit recordings and defined as the number of action potentials above the threshold divided by the recording time of 180 s. As shown in Fig. 1, action potentials appeared in bursts, separated by silent periods. Bursts were defined as a group of action potentials after a silent period of at least 0.5 s. The burst rate was calculated from the number of bursts occurring during the recording period (180 s). In order to quantify the peak firing rate, burst duration was subdivided into 50 ms-bins. Peak firing rate represents the highest firing frequency within a single burst. For statistical analysis, Student's t-test was used. Unless otherwise stated, results are given as mean (SEM). Concentration–response curves were fitted to Hill equations as described previously.13 Estimated EC50 values were derived from these fits.
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Effects of isoflurane and enflurane on discharge patterns
Extracellular recordings were performed from spinal interneurones visually identified in the ventral horn area, as described previously.16–18 The mean firing rates and the mean burst rates remained constant between 12 and 35 days in vitro, as previously reported.15 Cultures of this age were used for experiments.
Representative examples of the effects of isoflurane and enflurane on average firing patterns of spinal neurones are given in Figs 1 and 2. Figure 1A and B display original recordings showing action potentials which can be identified as vertical deflections grouped in bursts separated by silent periods. Binned spike data from the same experiments are illustrated in Fig. 1C and D. Note that isoflurane at a concentration of 1 MAC reduces both the number of action potentials per burst and the burst rate. Figure 1E and F display the time course of intraburst discharge rates calculated from averaged bursts. Figure 2 shows corresponding effects of 1 MAC enflurane.
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In our analysis on discharge patterns, we determined the effects of isoflurane and enflurane on peak firing rates and burst rates. The results are displayed in Fig. 3. Both anaesthetics decreased mean firing rates and peak firing rates in a similar manner (Fig. 3A and C). Figure 3B and D present the anaesthetic-induced changes in burst rates. Isoflurane and enflurane significantly depressed the burst rate at concentrations above 0.75 MAC. These data correspond to those recently reported for sevoflurane.15
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Effects of isoflurane and enflurane on discharge rates
The concentration-dependent effects of isoflurane and enflurane on average discharge rates of spinal neurones are summarized in Fig. 4. The EC50 value for isoflurane was calculated to be 0.52 (0.05) MAC [corresponding to 0.17 (0.02) mM, R2=0.975] and 0.80 (0.08) MAC for enflurane [corresponding to 0.50 (0.05) mM, R2=0.983]. With both anaesthetics, half-maximal depression was observed at concentrations below the EC50 for immobility.
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Effects of isoflurane and enflurane in the presence of antagonists of GABAA or glycine receptors
Experiments using antagonists were performed with the rationale that a decreased efficacy of an anaesthetic to reduce mean firing rate in the presence of a specific antagonist is an indication that the anaesthetic acts via the corresponding receptor–ion channel complex.3 6 15 The effects of the GABAA receptor antagonist bicuculline (100 µM), the glycine receptor antagonist strychnine (1 µM), and a combination of both antagonists on ongoing neuronal activity in spinal cord cultures were reported recently.15 Both antagonists accelerated mean firing rate and produced a moderate depression of the burst rate.15 The effectiveness of strychnine 1 µM in saturating glycine receptors has been shown previously in the rat spinal cord in accordance with the high receptor affinity of this antagonist.19 As a bicuculline concentration of 20 µM was not sufficient to completely block GABAA receptors in cultured neocortical slices, we used a bicuculline concentration of 100 µM, which was demonstrated to exert a complete blockade of GABAA receptor-mediated conductance in organotypic neocortical slices.20
Drug interaction experiments were performed with concentrations of isoflurane and enflurane which exerted a depression in spontaneous activity of approximately 60% and can therefore be regarded as equi-effective. These concentrations were 0.24 mM in the case of isoflurane (corresponding to 0.75 MAC) and 0.62 mM (corresponding to 1 MAC) for enflurane.
Figure 5 shows the effects of isoflurane and enflurane in the presence of bicuculline (100 µM), strychnine (1 µM), a combination of both antagonists and in the absence of either. We tested the hypothesis that the depressant effects of 0.75 MAC isoflurane or enflurane 1 MAC on discharge rates did not differ in the presence or absence of bicuculline. This hypothesis was rejected for both anaesthetics although the extent of depression differed. Bicuculline decreased isoflurane-induced depression of ongoing activity by approximately 36% (t-test, P<0.001, n=9, Fig. 5A) and enflurane-induced depression by 26% (t-test, P<0.05, n=8, Fig. 5B). We conclude that enhanced GABAA-mediated synaptic inhibition contributed to the decrease in neuronal activity induced by isoflurane 0.75 MAC or enflurane 1 MAC.
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Decreased efficacy in strychnine-treated slices is an indication that isoflurane or enflurane act at the glycine receptor–ion channel complex.21 22 We tested the hypothesis that depression of average firing rates by sevoflurane 0.75 MAC or enflurane 1 MAC will not differ in the presence or absence of strychnine. This hypothesis was rejected for isoflurane and enflurane, as strychnine reduced the effects of isoflurane on mean firing rate by 39% (t-test, P<0.001, n=8, Fig. 5A) and the effects of enflurane by 29% (t-test, P<0.05, n=9, Fig. 5B).
The combination of bicuculline and strychnine reduced the depression of action potential firing of isoflurane 0.75 MAC by 75% (t-test, P<0.001, n=10) and of enflurane 1 MAC by 55% (t-test, P<0.001, n=9), indicating that enhancement of GABAergic and glycinergic synaptic transmission was responsible for a large part but not for all anaesthetic depressant actions (Fig. 5A and B). Figure 6 shows an estimation how GABAA, glycine and other targets contribute to the overall effects of isoflurane and enflurane on ongoing activity. Relative fractions were calculated from the data shown in Fig. 5.
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Discussion |
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In the present study, we examined the effects of isoflurane and enflurane on action potential activity in spinal slice cultures. Cultures of spinal cord slices were previously established to investigate isolated pattern-generating networks in vitro.11 17 Pattern-generating neural networks initiate and control stereotyped movements such as breathing or locomotor rhythms such as running by providing the timing of motoneurone discharge. The central components of these networks are capable of producing rhythmic patterns of activity,23 and anaesthetic-induced changes in ongoing activity reflect corresponding changes in the excitability of spinal neurones in vitro.15 The anaesthetic endpoint of immobilization is defined by the abolition of organized movements and suppression of spinal interneuronal network activity can be regarded as essential to eliminate coordination of movements.24
The role of GABAA receptors in mediating spinal effects of general anaesthetics is a matter of ongoing research. Studies on knock-in mice have shown that propofol and etomidate cause immobility predominantly via GABAA receptors containing ß3 subunits.8 However, in clinical settings these anaesthetics are used to produce hypnosis rather than immobility. Furthermore, studies investigating the requirements of neuromuscular blocking agents during anaesthesia maintained with either volatile anaesthetics or propofol have demonstrated that propofol, unlike volatile anaesthetics, did not decrease the requirement for neuromuscular blocking agents, thereby indicating a limited efficacy in depressing painful stimulus induced movements.25 26 In contrast, volatile anaesthetics are potent immobilizers, implying a major difference in molecular targets of volatile and i.v. anaesthetics. There is growing evidence that volatile anaesthetics depress spinal neurones via multiple molecular targets at concentrations close to MACimmobility. In the present study, we asked whether isoflurane and enflurane inhibit spinal neurones in part via GABAA and glycine receptors. Our major finding is that these receptors contribute almost equally to the depressant effects of both volatile anaesthetics on ventral horn neurones in cultured spinal slices. The concentration of isoflurane reducing mean firing rates of spinal neurones by half (EC50) was 0.17 (0.02) mM (corresponding to 0.52 MACimmobility). This value compares well with the concentration causing half-maximal depression of F-wave amplitude and F-wave persistence (EC50 0.4 MACimmobility)27 and H-reflex amplitude (EC50 0.6 MACimmobility)28 in humans. Enflurane reduced spontaneous action potential firing of spinal neurones with an EC50 of 0.50 (0.05) mM (corresponding to 0.80 MACimmobility). Hence, we conclude that the concentrations at which isoflurane and enflurane depressed spinal interneurones in our study are of clinical relevance.
Our findings are in excellent accordance with results published by Wong and colleagues,29 who investigated the effects of enflurane on neuronal responses evoked by electrical stimulation in acutely isolated spinal slices and in whole spinal cord preparations. They reported that the population excitatory potential (an electric correlate of the monosynaptic reflex) and the dorsal root potential were depressed by half at concentrations corresponding to about 0.7 MACimmobility, which is close to that reported in the present study. Furthermore, Wong and colleagues29 administered specific antagonists of GABAA and glycine receptors before and during enflurane application. They concluded that about 30% of the depressant effects of enflurane in the spinal cord are mediated via GABAA receptors whereas approximately 20% are mediated via glycine receptors. Again, these estimates closely match the results of the present work. Figure 6 indicates corresponding values of 26% for GABAA and 29% for glycine receptors. Thus, the fraction of inhibition mediated via GABAA receptors in conjunction with glycine receptors is close to 50% in both studies.
When comparing the effects of enflurane with those of isoflurane and sevoflurane,15 it can be seen that, similar to enflurane, the latter anaesthetics act in part via glycine and GABAA receptors at clinically relevant concentrations. However, the depression mediated by GABAA and glycine receptors is 75% for isoflurane and 83% for sevoflurane and therefore higher compared with enflurane (55%). A difference between enflurane and isoflurane was also observed regarding their specific actions at the molecular level. While both anaesthetics prolonged current decays of action potential-independent GABAergic IPSCs they decreased the amplitudes to different extents. Enflurane, in contrast to isoflurane, exerted a pronounced depression of IPSC amplitudes.30
Sonner and colleagues3 suggested that GABAA receptors are not a dominant target for halogenated ether anaesthetics in producing immobility. Our finding that GABAA receptors account for approximately 30% of the depressant effects of isoflurane and enflurane is in good agreement with this hypothesis. Furthermore, we observed that glycine receptors are almost equally important. This result is consistent with findings of Wong and colleagues,29 who provided evidence that besides GABAA and glycine receptors a direct inhibitory action on glutamate receptors accounted for nearly 30% of the depressant effect of enflurane.
In conclusion, there is no dominant or major molecular target by which volatile anaesthetics depress spinal neurones, thus causing immobility. Rather, volatile anaesthetics depress spinal networks via multiple molecular targets, each contributing a minor fraction of 30% or less. This hypothesis allows the prediction that in animals in which a single molecular target for volatile anaesthetics is knocked out or rendered insensitive, a shift in MACimmobility towards higher values should be affected only moderately. Results from in vivo studies using knock-in mice support this prediction: in ß3 knock-in mice carrying a point mutation in the ß3 subunit of the GABAA receptor the MACimmobility was increased by 15% for enflurane8 and by 24% for isoflurane.10 A similar increase in MACimmobility was observed in TREK-1 knock-out mice for sevoflurane (11%), suggesting that effects of volatile anaesthetics on potassium channels also contribute to immobility.31
In summary, our results are in line with the view that volatile anaesthetics produce immobility via a multitude of ion channels including GABAA, glycine and glutamate receptors and potassium channels, and effects on GABAA and glycine receptors contribute equally to depression of ventral horn neurones. In contrast to volatile anaesthetics, the immobilizing effects of i.v. anaesthetics such as propofol and etomidate are almost exclusively mediated via GABAA receptors.6 8 15 Clearly the spectrum of molecular structures in the spinal cord recruited by volatile anaesthetics is larger compared with i.v. anaesthetics, which can explain their effectiveness in producing immobility.
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Acknowledgments |
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The authors wish to thank Claudia Holt for the excellent technical assistance. This study was supported by a grant of the Bundesministerium fuer Verteidigung (M SAB1 3A014) to C.G.
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References |
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1 Collins JG, Kendig JJ, Mason P. Anaesthetic actions within the spinal cord: contributions to the state of general anaesthesia. Trends Neurosci 1995; 18:549–53[CrossRef][Web of Science][Medline]
2 Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anaesthetics. N Engl J Med 2003; 348:2110–24
3 Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anaesthetics and immobility: mechanisms, mysteries, and minimum alveolar anaesthetic concentration. Anesth Analg 2003; 97:718–40
4 Antognini JF and Carstens E. In vivo characterization of clinical anaesthesia and its components. Br J Anaesth 2002; 89:156–66
5 Antognini JF, Carstens E, Atherley R. Does the immobilizing effect of thiopental in brain exceed that of halothane? Anesthesiology 2002; 96:980–6[CrossRef][Web of Science][Medline]
6 Sonner JM, Zhang Y, Stabernack C, Abaigar W, Xing Y, Laster MJ. GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not ketamine or isoflurane in a dose-related manner. Anesth Analg 2003; 96:706–12
7 Zhang Y, Sonner JM, Eger EI, et al. Gamma-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane. Anesth Analg 2004; 99:85–90
8 Jurd R, Arras M, Lambert S, et al. General anaesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 2003; 17:250–2
9 Liao M, Sonner JM, Jurd R, et al. Beta3-containing gamma-aminobutyric acidA receptors are not major targets for the amnesic and immobilizing actions of isoflurane. Anesth Analg 2005; 101:412–8
10 Lambert S, Arras M, Vogt KE, Rudolph U. Isoflurane-induced surgical tolerance mediated only in part by beta3-containing GABA(A) receptors. Eur J Pharmacol 2005; 516:23–7[CrossRef][Web of Science][Medline]
11 Braschler UF, Iannone A, Spenger C, Streit J, Luscher HR. A modified roller tube technique for organotypic cocultures of embryonic rat spinal cord, sensory ganglia and skeletal muscle. J Neurosci Methods 1989; 29:121–9[CrossRef][Web of Science][Medline]
12 Gahwiler BH. Organotypic monolayer cultures of nervous tissue. J Neurosci Methods 1981; 4:329–42[CrossRef][Web of Science][Medline]
13 Antkowiak B and Helfrich FC. Effects of small concentrations of volatile anaesthetics on action potential firing of neocortical neurones in vitro. Anesthesiology 1998; 88:1592–605[Web of Science][Medline]
14 Franks NP and Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367:607–14[CrossRef][Medline]
15 Grasshoff C and Antkowiak B. Propofol and sevoflurane depress spinal neurones in vitro via different molecular targets. Anesthesiology 2004; 101:1167–76[Web of Science][Medline]
16 Streit J, Spenger C, Luscher HR. An organotypic spinal cord–dorsalroot ganglion–skeletal muscle coculture of embryonic rat. II. Functional evidence for the formation of spinal reflex arcs in vitro. Eur J Neurosci 1991; 3:1054–68[CrossRef][Web of Science][Medline]
17 Spenger C, Braschler UF, Streit J, Luscher HR. An organotypic spinal cord–dorsal root–ganglion skeletal muscle coculture of embryonic rat. I. The morphological correlates of the spinal reflex arc. Eur J Neurosci 1991; 3:1037–53[CrossRef][Web of Science][Medline]
18 Ballerini L and Galante M. Network bursting by organotypic spinal slice cultures in the presence of bicuculline and/or strychnine is developmentally regulated. Eur J Neurosci 1998; 10:2871–9[CrossRef][Web of Science][Medline]
19 Bracci E, Ballerini L, Nistri A. Localization of rhythmogenic networks responsible for spontaneous bursts induced by strychnine and bicuculline in the rat isolated spinal cord. J Neurosci 1996; 16:7063–76
20 Antkowiak B. Different actions of general anaesthetics on the firing patterns of neocortical neurones mediated by the GABA(A) receptor. Anesthesiology 1999; 91:500–11[CrossRef][Web of Science][Medline]
21 Zhang Y, Laster MJ, Hara K, et al. Glycine receptors mediate part of the immobility produced by inhaled anaesthetics. Anesth Analg 2003; 96:97–101
22 Cheng G and Kendig JJ. Pre- and postsynaptic volatile anaesthetic actions on glycinergic transmission to spinal cord motor neurones. Br J Pharmacol 2002; 136:673–84[CrossRef][Web of Science][Medline]
23 Marder E and Calabrese RL. Principles of rhythmic motor pattern generation. Physiol Rev 1996; 76:687–717
24 Jinks SL, Atherley RJ, Dominguez CL, Sigvardt KA, Antognini JF. Isoflurane disrupts central pattern generator activity and coordination in the lamprey isolated spinal cord. Anesthesiology 2005; 103:567–75[CrossRef][Web of Science][Medline]
25 Lowry DW, Mirakhur RK, McCarthy GJ, Carroll MT, McCourt KC. Neuromuscular effects of rocuronium during sevoflurane, isoflurane, and intravenous anaesthesia. Anesth Analg 1998; 87:936–40
26 Motamed C and Donati F. Sevoflurane and isoflurane, but not propofol, decrease mivacurium requirements over time. Can J Anaesth 2002; 49:907–12[Web of Science][Medline]
27 Zhou HH and Zhu C. Comparison of isoflurane effects on motor evoked potential and F wave. Anesthesiology 2000; 93:32–8[CrossRef][Web of Science][Medline]
28 Zhou HH, Mehta M, Leis AA. Spinal cord motoneuron excitability during isoflurane and nitrous oxide anaesthesia. Anesthesiology 1997; 86:302–7[CrossRef][Web of Science][Medline]
29 Wong SM, Cheng G, Homanics GE, Kendig JJ. Enflurane actions on spinal cords from mice that lack the beta3 subunit of the GABA(A) receptor. Anesthesiology 2001; 95:154–64[CrossRef][Web of Science][Medline]
30 Banks MI and Pearce RA. Dual actions of volatile anaesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects. Anesthesiology 1999; 90:120–34[CrossRef][Web of Science][Medline]
31 Heurteaux C, Guy N, Laigle C, et al. TREK-1, a K(+) channel involved in neuroprotection and general anesthesia. EMBO J 2004; 23:2684–95[CrossRef][Web of Science][Medline]
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