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GENERAL ARTICLES

Local GABA_A Receptor Blockade Reverses Isoflurane’s Suppressive Effects on Thalamic Neurons In Vivo

Christiane Vahle-Hinz, PhD^*, Oliver Detsch, MD, Matthias Siemers, MSc^*, Eberhard Kochs, MD, and Burkhart Bromm, MD, PhD^*

*Institut für Physiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; and Klinik für Anaesthesiologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Address correspondence and reprint requests to Dr. Christiane Vahle-Hinz, Institut für Physiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Address e-mail to vahle{at}uke.uni-hamburg.de

	Abstract

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Many in vitro effects of volatile anesthetics are known, but the mechanisms of action are still under debate. Because suppression of sensory perception is one of the major goals of general anesthesia, we studied the effects of isoflurane on the processing of somatosensory information in anesthetized rats. Local iontophoretic administration of the -aminobutyric acid-A (GABA_A) receptor antagonist bicuculline in the thalamic ventral posteromedial nucleus reversed suppressive effects of isoflurane on thalamocortical relay neurons (TCNs). The action potential discharges of TCNs (n = 23) in response to defined mechanical stimulation of receptive fields seen with small concentrations of isoflurane (0.79% ± 0.01%, mean ± SEM) were suppressed under large concentrations (1.44% ± 0.04%). In addition, the tonic response pattern was lost, which initially encoded the information about the stimulus features. In 70% of TCNs, bicuculline administration reestablished the initially present tonic response pattern under large isoflurane concentrations. These results indicate that isoflurane suppresses somatosensory information transfer at the thalamic level in vivo, apparently by enhancing thalamic GABA_A receptor-mediated inhibition.

Implications: Isoflurane actions in the thalamus suppressed the transmission of tactile input to the cortex. This effect was reversed by removal of thalamic inhibition. Suppression of sensory perception under general anesthesia, therefore, may result in part from isoflurane’s interaction with thalamic -aminobutyric acid-A receptors.

	Introduction

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There is controversy about the exact mechanisms of action of volatile anesthetics. Suppression of neuronal electrical activity by volatile anesthetics has been ascribed to interactions with -aminobutyric acid-A (GABA_A) receptors (1–4) and other ligand-gated (3), as well as voltage-gated, ion channels (1). Furthermore, some studies also report that isoflurane (ISO) induces alterations of intrinsic membrane properties of neurons (5,6). It is unclear which of the effects of volatile anesthetics demonstrated in vitro are important for producing relevant in vivo effects seen on the behavioral level. There is increasing evidence from recent experiments with different in vitro brain preparations (7–9) that the actions of volatile anesthetics are mediated mainly by an enhancement of GABA_A-receptor-mediated synaptic inhibition. The relative impact of effects demonstrated in those artificial preparations, however, has to be investigated in fully intact in vivo preparations.

We used the trigeminal somatosensory system of the rat as a model. In rats, facial whiskers arranged around the snout drive all types of mechanoreceptors also present in the human skin; therefore, the whisker system has been used extensively as a model for studies of sensory information processing (10). Tactile events are encoded in trains of action potentials that contain information about stimulus features (intensity, duration, velocity, and location on the body surface). Thus, recording response discharges evoked by defined stimuli in somatosensory neurons allows one to evaluate the biologic significance of anesthetic-induced changes of action potential firing. Facial tactile information is conveyed via the brainstem and the ventral posteromedial (VPM) nucleus of the thalamus to the primary somatosensory cortex (Fig. 1a). This pathway uses the excitatory amino acid glutamate as a transmitter (11). By way of the GABAergic inhibitory input from the thalamic reticular nucleus (TRN), somatosensory information is modulated in VPM thalamocortical relay neurons (TCNs) (10,12–14).

View larger version (34K): [in this window] [in a new window]   Figure 1. Recording site and response characteristics of thalamic neurons under isoflurane (ISO) anesthesia. (a) Schematic representation of the ascending pathway of the somatosensory system transmitting tactile information from mechanoreceptors of the facial skin to the primary somatosensory cortex (SI). The tungsten microelectrode/multibarrel assembly allowed extracellular single-unit recordings from thalamocortical relay neurons of the thalamic ventral posteromedial nucleus (VPM) and local iontophoresis of the -aminobutyric acid-A receptor agonist muscimol (MUSC) and the antagonist bicuculline (BIC). GABAergic synapses on VPM neurons derive from the thalamic reticular nucleus (TRN). (b) Conversion of the tonic response (upper trace) to movement of a whisker to an ON response (middle trace) by increased concentration of ISO. Original spike records. The bars represent the respective response components in relation to the ramp and plateau parts of the trapezoidal stimulus (lowest trace).

	Methods

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The experiments were performed, after approval of the Hamburg University Animal Research Committee, on eight adult Wistar rats (380–550 g body weight) by using methods reported previously (15). Briefly, anesthesia was induced by intraperitoneal injection of ketamine (100 mg/kg). The trachea and femoral vein were cannulated for mechanical ventilation of the lungs and (during the recording sessions) the administration of vecuronium bromide (4 mg · kg^-1 · h^-1) for muscle relaxation, respectively. End-tidal CO₂ concentration and body temperature were continuously monitored and kept in normal ranges. Heart rate was monitored via electrocardiogram. Throughout surgical preparation, anesthesia was maintained by ISO at 1.0%–1.6% end-tidal concentration (in oxygen); inspired and end-tidal ISO concentrations were monitored continuously (Capnomac; Datex, Helsinki, Finland). The animals were monitored for adequacy of anesthetic depth, which was based on the absence of movement and heart rate reactions. If such signs were present, ISO was increased immediately. During the recording sessions, the rats were allowed to recover periodically from immobilization to ensure the adequacy of anesthetic depth. The animal’s head was mounted in a stereotaxic holder with blunt ear bars. A lateral 3-mm square craniotomy was performed, and the dura mater was removed. At the end of the experiments, the animals were killed with an overdose of pentobarbital.

The combined recording/iontophoresis electrodes consisted of a tungsten electrode (impedance at 1 kHz, 2 M) glued alongside a five-barrel micropipette (diameter: 10–20 µm) with the tip of the recording electrode protruding between 30 and 100 µm. The following drugs were used for iontophoresis: the competitive GABA_A receptor antagonist bicuculline methochloride (BIC) (5–10 mM in 165 mM NaCl, pH 3.0), the GABA_A receptor/chloride channel blocker picrotoxin (5 mM in 165 mM NaCl, pH 3.5), the GABA_A receptor agonist muscimol (MUSC) (10 mM in 165 mM NaCl, pH 3.5), GABA (0.5 M, in distilled water, pH 3.5), and 0.9% NaCl. For the local drug application, a four-channel iontophoresis device with a current-balancing unit (NPI Electronic, Tamm, Germany) was used. Drugs were ejected with positive currents, negative retaining currents were applied at all times outside periods of drug ejection, and controls for pH and current were performed routinely. In three cases, BIC and picrotoxin were administered sequentially to the same neurons and elicited parallel effects. This demonstrates that the effects of BIC were mediated, in our study, specifically via the GABA_A receptor/channel complex and not via interactions with spike afterhyperpolarizations mediated by Ca²⁺-activated K⁺ channels. It was important to eliminate this potential effect because BIC’s effects on GABA_A receptors and K⁺ channels may have resulted in similar functional consequences (16).

The recording/iontophoresis electrode was inserted stereotaxically into the VPM in dorsoventral penetrations, and extracellular single-unit activity was recorded. The neuron’s association to the VPM was determined by their facial low-threshold receptive fields and the well known features of VPM neurons: the somatotopic sequence of neighboring neurons with small receptive fields and the brisk responses to mechanical stimulation of whiskers, fur, and skin (10,12,17). The neuronal activity was amplified, filtered, and displayed on an oscilloscope from which original recordings were photographed. The data were stored on a digital tape recorder, and off-line analysis was performed by means of a window discriminator, an interface, and a computer program (Spike2 software; Cambridge Electronic Design, Cambridge, UK).

Low-threshold mechanoreceptive neurons responding tonically to movement of whiskers were selected (Fig. 1b) (15) and initially characterized under 0.6% or 0.8% ISO. Trapezoidally shaped stimuli were applied to single whiskers glued to the probe of a feedback-controlled electromechanical stimulator (Somedic, Horby, Sweden). Peristimulus time histograms (PSTHs) (bin width 1 ms) were calculated from the neuronal responses to 20 consecutive stimuli (duration, 400–600 ms) delivered at 2.5-s intervals. From these PSTHs, neuronal activities were assessed as mean discharge frequencies (spikes per second): the response activity per stimulus was measured for the entire stimulus duration (total response), as well as separately for the ramp (movement response) and the plateau parts (plateau response), and was determined as discharge rate above continuing activity. The continuing activity was measured from the 1-s period immediately before stimulus onset.

The same experimental sequence was applied to all neurons:

1. 1. ISO low (baseline): baseline condition with 0.6% or 0.8% end-tidal ISO; baseline anesthesia was adapted to the individual rat’s susceptibility to ISO.
   
2. 2. ISO high: increase of ISO by at least 0.4% to induce a conversion of tonic to ON response pattern (Fig. 1b) (15).
   
3. 3. ISO high + BIC: iontophoresis of BIC with large ISO concentration; the dose of BIC was targeted at a constant effect on response activity without affecting continuing activity.
   
4. 4. ISO high, recovery from BIC: termination of BIC administration under maintained large ISO concentration.
   
5. 5. ISO low, recovery from ISO high: return to baseline ISO concentration (0.6% or 0.8% ISO).
   

Equilibration periods for changes of ISO concentration of at least 10 min were observed before neuronal activity was recorded. The final recovery data were taken to ensure that the neuronal discharge characteristics were unchanged over time.

The effects of increases in inspired ISO concentrations and the administration of BIC on neuronal activities were analyzed with multiple Wilcoxon’s tests with Bonferroni corrections, and P < 0.05 was considered significant. With the large ISO concentration, the recurrence of discharges during the plateau part of the stimulus with a rate of at least 50% of baseline plateau response activity (at ISO low) was the criterion for reversal of ON responses to tonic responses during BIC administration (ISO high + BIC).

	Results

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The effects of clinically relevant concentrations of ISO alone and in the presence of the GABA_A-receptor antagonist BIC, administered iontophoretically, were investigated in 23 low-threshold mechanoreceptive TCNs of the rat’s VPM. The tonically responding TCNs discharge during the plateau of a trapezoidally shaped movement of whiskers, encoding the intensity (displacement amplitude) and duration of the stimulus (plateau response). These neurons also discharge during the ramp part of the stimulus, encoding the velocity of the whisker movement (movement response). An example of a typical tonic response is shown in Figure 1b (upper trace). An increase of ISO from 0.8% to 1.8% resulted in a conversion of the tonic response to an ON response in this neuron, i.e., all stimulus-encoding features of the response are absent but the stimulus onset (Fig. 1b, middle trace). Such a conversion was induced in the population of neurons by increasing ISO (by 0.4%) to 1.0%–1.8% (ISO high).

The local administration of BIC with ISO high markedly increased the response activity of all neurons investigated. The BIC effects were dose dependent, i.e., they increased with the current and duration of iontophoretic administration. The ON responses were reversed again to tonic responses in 70% of the converted neurons by BIC iontophoresis. Although no reversal to tonic response pattern was seen in the remaining six neurons, BIC effected a marked increase in movement discharge.

The original spike records of Figure 2 demonstrate as an example the dose-dependent reversal of the tonic response of a TCN under large ISO concentration with time of BIC administration. The increase in ISO resulted in a conversion of the tonic response present under baseline anesthesia (Fig. 2a) to an ON spike (Fig. 2b). After 7 min of ejection of 60 nA BIC, spikes were elicited during the entire rising ramp of the stimulus, i.e., the forward movement of the whisker (Fig. 2c). Then, spikes also reappeared during the plateau part of the stimulus, and after 15 min of BIC ejection, the tonic response was reestablished with characteristics equal to those under baseline anesthesia (Fig. 2d). After termination of BIC ejection, the suppressant effect of the large ISO dose dominated, and again only ON spikes were elicited (Fig. 2e). The tonic response recovered when the ISO concentration was returned to baseline level (Fig. 2f).

View larger version (31K): [in this window] [in a new window]   Figure 2. Bicuculline (BIC) reverses the isoflurane (ISO)-induced inhibition of the tonic response of a thalamocortical relay neuron. The tonic response present under baseline anesthesia (a) is converted to an ON spike under 1.0% ISO (b). During ejection of 60 nA BIC, the response recovers dose-dependently with time: first the movement response appears (c), then the plateau response (d). After termination of bicuculline administration, the response is reduced again to an ON spike by ISO (e). The tonic response recovers after return to baseline anesthesia (f). Original spike records of single responses to trapezoidal movement of a whisker (lowest traces).

View larger version (18K): [in this window] [in a new window]   Figure 3. -Aminobutyric acid-A (GABAA) receptor mechanisms are involved in inhibition of thalamic responses. The tonic responses to trapezoidal movement of a whisker (lowest traces) present under baseline anesthesia (a) are suppressed by the administration of the GABAA agonist muscimol (MUSC) (b). The MUSC-induced inhibition is antagonized by concomitant administration of bicuculline (BIC) (c). The response/suppressant effect of 1.2% isoflurane (ISO) (d) is reversed by BIC administration (e), which in turn is antagonized by MUSC (f). Stepwise recovery from drug administration (g, h) as well as from ISO high (i), show reproducibility of the effects. Peristimulus time histograms (bin width 1 ms, n = 20 stimuli).

View larger version (20K): [in this window] [in a new window]   Figure 4. Pooled data analysis. Attenuation of response discharges of all 23 thalamocortical relay neurons by large isoflurane (ISO) concentrations (ISO high) and reversal of ISO-induced suppression by bicuculline (BIC) iontophoresis (ISO high + BIC). The local administration of the -aminobutyric acid-A receptor antagonist BIC significantly increased the response activity measured during the entire stimulus (a, total response activity), as well as during the ramp part of the stimulus (b), in all neurons. Seven neurons were tested with two and one neuron with three different large ISO concentrations; therefore, the total number of trials is 32. The plateau response activity (c), analyzed for the neurons that showed a reversal from ON to a tonic response pattern during BIC administration, was also increased to rates not different from baseline. ISO low, baseline = 0.6% or 0.8% ISO before ISO increase; ISO high = 1.0%–1.8% ISO; ISO high + BIC = BIC iontophoresis under high ISO; ISO high, recovery from BIC = recovery from BIC administration under high ISO; and ISO low recovery from ISO high = return to baseline ISO concentration. The boxes and whiskers represent the 25th, 50th, and 75th, as well as 10th and 90th percentiles. *P < 0.001 versus ISO low at baseline.

	Discussion

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The main result of our study is that the local thalamic administration of the GABA_A receptor antagonist BIC reversed the ISO-induced effects on functional response characteristics in more than two-thirds of TCNs studied. This suggests that the potentiation of GABA_Aergic inhibition—which in vitro studies have demonstrated to be one of ISO’s predominant mechanisms—may in fact play an important role in its in vivo anesthetic action. This is the first report that shows that a prototype volatile anesthetic interacts with thalamic inhibitory mechanisms leading to a blockade of sensory information transfer to the cerebral cortex. This block affected specific components of response characteristics, reflecting the ramp and plateau parts of the mechanical stimulus. In deep anesthesia, thereby, the ability of thalamic, and hence also cortical, neurons to discriminate stimulus features—such as movement, intensity, and duration—disappears. Information about painful stimuli transmitted by nociceptive neurons may also be blocked by large ISO concentrations at the thalamic level, as preliminary data show (18).

The dose-dependent suppressive effects of ISO on TCN continuing and response activity have been demonstrated previously by using systematic 0.2% stepwise increases of ISO concentration (15). Apart from the quantitative reduction in response activity, we also noted an alteration of the response characteristics. Therefore, in this study, we sought to study the mechanisms underlying this effect on the functional response characteristics. Hence, the increase in ISO concentration was targeted this time at that necessary for response conversion. Again, a clear dose-dependent effect was seen because response conversion occurred after almost doubling the baseline ISO concentration. Similarly, doses of iontophoretically administered drugs were targeted at a constant effect on response activity without affecting continuing activity. Drug doses during iontophoresis are difficult to determine because they depend on the time and current of application, the distance and geometry of the pipette tips with respect to the recorded neuron, and the diffusion within the tissue, as well as the uptake mechanisms present; thus, the dose had to be adapted to each neuron (19). When BIC is administered in larger doses, apart from its actions at GABA_A receptors, it may directly excite neurons via extrasynaptic actions and thus induce spontaneous (continuing) activity, producing uncontrolled effects. Ketamine was used to induce general anesthesia and to facilitate tracheotomy. After we placed the tracheal catheter, ISO was administered as the only anesthetic for the remainder of the experiment. We consider it unlikely that any residual ketamine effects were still present during neuronal data sampling because the recording sessions commenced at least three hours after the administration of the short-acting induction drug. Additionally, residual ketamine effects would have been noted by comparison of the initial baseline recordings with the recovery recordings (up to four hours later); this comparison, however, revealed no differences (Fig. 4).

The GABAergic synapses on the rat’s TCNs derive exclusively from the TRN (Fig. 1a), because interneurons within VPM are virtually lacking (10,12). Several studies have indicated that inhibitory mechanisms effected by GABAergic axon terminals of TRN neurons control the functional response patterns of VPM neurons; thus, they control the nature of information that is conveyed to the cortex (13). In contrast to the ISO-induced response conversion from tonic to ON responses seen here and in the previous study (15) for TCNs, the tonic response patterns of their afferent inputs (the trigeminothalamic fibers) did not change under ISO concentrations up to 2.0%: only their response magnitude was slightly reduced (15). These results suggest that ISO attenuates the output of somatosensory information of the thalamus, whereas its input is affected to a lesser degree. This is also corroborated by the present findings showing that blockade of thalamic GABA_A receptors under large concentrations of ISO did not induce an increase in continuing activity but revealed a recovery of stimulus-evoked response pattern and magnitude in most neurons. Similar findings have been reported from studies of the extracranial somatosensory system (20,21). However, it is not surprising that the thalamic input is affected to some degree by ISO, because others have described effects of volatile anesthetics on dorsal horn neuronal activity (22) that have been ascribed partly to interactions with GABA_Aergic transmission (23). Therefore, actions of ISO at subthalamic levels may have contributed to the failure to reestablish the tonic response pattern in less than one-third of the TCNs studied, despite thalamic GABA_A antagonism.

Another potential cause for the preserved ON response pattern despite BIC administration in some TCNs may be a suppression of the glutamatergic signal transmission, because in vitro studies have demonstrated depressive actions of volatile anesthetics on glutamatergic transmission at both presynaptic and postsynaptic sites (24–26). However, signal transmission from trigeminothalamic fibers to TCNs expresses a high safety factor under various anesthetic conditions (12,13,27). Another glutamatergic influence onto thalamic neurons is exerted by descending corticothalamic fibers (10,12). This, however, influences both TCNs and TRN neurons and therefore might serve to increase or decrease thalamocortical signal transmission. It is also conceivable that additional remote effects of ISO on the cortical or the brainstem inputs to TRN may enhance its activity.

Nonreceptor mediated effects, however, may play a role as well; Ries and Puil (5,6) showed in brain slices that ISO induced a hyperpolarization and shunting of voltage-dependent Na⁺ and Ca⁺ currents. Thereby, neuronal excitability was reduced and tonic firing to depolarizing pulses prevented. With respect to our results, it seems, however, that this effect may play only a minor role, because removal of GABA_A-receptor-mediated hyperpolarization under a large ISO concentration allowed the neurons to discharge tonically in response to their afferent inputs no differently than under baseline anesthesia. Also, the fact that the continuing activity, definitely suppressed by ISO, was resistant to BIC in doses that reversed the response activity points toward GABA_A-receptor-mediated effects. The continuing activity of TCNs, in contrast to their response activity, is independent of GABAergic control from the TRN, because lesioning the TRN had no effect on continuing activity (28). Nevertheless, there is controversy regarding the importance of potential actions of volatile anesthetics on membrane excitability (1,26).

There is ample evidence from many in vitro studies showing that enhancement of GABA_A-receptor-mediated inhibition may be a major mechanism of action of volatile anesthetics (1–4). In one study, by using an organotypic neocortical brain slice preparation, Antkowiak (8) demonstrated an inhibition of spontaneous action potential discharges by ISO, which was reversed by more than 90% after the administration of BIC to the bathing solution. In agreement with previous findings from various brain tissue preparations, such as hippocampal brain slices (7) and autaptic cultures of hippocampal neurons (9), these results indicated that the volatile anesthetic acted predominantly on GABA_A receptors. Therefore, we conclude from our results that the potentiation of GABA_A-receptor-mediated synaptic inhibition seems to play an important role in ISO-induced suppression of TCN activity, outweighing potential effects on other sites, such as glutamatergic synaptic transmission or membrane properties.

	Acknowledgments

 
Supported in part by the Institute of Physiology and Department of Anesthesiology.

We would like to thank Ms. Maren Kurschat for expert technical assistance.

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