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Anesth Analg 2003;96:1354-1359
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Enflurane Decreases Glutamate Neurotransmission to Spinal Cord Motor Neurons by Both Pre- and Postsynaptic Actions

Gong Cheng, MD, and Joan J. Kendig, PhD

Department of Anesthesia, Stanford University School of Medicine, Stanford, California

Address correspondence to Joan J. Kendig, MD, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305. Address e-mail to kendig{at}stanford.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Summary
 References
 
We have previously reported volatile anesthetic actions on glycinergic inhibitory transmission to spinal motor neurons. The present study is a comparable set of experiments on glutamatergic excitatory transmission. We tested the hypothesis that the balance between excitation and inhibition is shifted toward inhibition by larger depressant actions on excitation. Patch-clamp techniques were used to study spontaneous and evoked glutamate {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid currents in rat spinal cord slices. Enflurane (0.6 mM, 1 minimum alveolar anesthetic concentration) significantly decreased spontaneous miniature current frequencies either when sodium channels were blocked (miniature excitatory postsynaptic currents, mEPSCs), or when sodium channels were not blocked (spontaneous excitatory postsynaptic currents, sEPSCs). Enflurane did not affect mEPSC or sEPSC amplitude or kinetics. The effects on mEPSCs and sEPSCs did not differ. Enflurane significantly decreased both amplitude and area of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-evoked currents with no change in kinetics (P < 0.05 and 0.01, respectively). In contrast, enflurane increased miniature glycinergic current frequency when sodium channels were blocked, and prolonged glycinergic current duration. Enflurane actions on glutamatergic excitatory transmission are purely depressant both pre- and postsynaptically, whereas glycinergic inhibition is enhanced presynaptically under some conditions, and always prolonged postsynaptically. Thus, enflurane shifts the balance between synaptic excitation and inhibition in the direction of inhibition.

IMPLICATIONS: Explanations proposed for anesthetic-induced central nervous system depression include enhancement of synaptic inhibition and depression of excitation. The results reported herein suggest that, in the case of enflurane, the mechanism is a shift in the balance toward inhibition. Excitation is uniformly depressed by multiple mechanisms, whereas some anesthetic actions tend to enhance inhibition.


   Introduction
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 Abstract
 Introduction
Methods
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 References
 
The inhibitory chloride channels, namely the {gamma}-amino butyric acid A (GABAA) and glycine receptors, have received major attention as target sites for anesthetic action (1,2). However, several studies have shown that at least some inhaled anesthetics act on glutamate receptors as well (3–7). Halothane seems to depress glutamatergic synaptic transmission in hippocampus by both presynaptically inhibiting transmitter release and postsynaptically depressing glutamate currents (8). In spinal cord, the site that determines the anesthetic end point of immobility in response to a noxious stimulus (minimum alveolar anesthetic concentration [MAC]) (9–12), enflurane depresses glutamate-evoked inward currents independent of actions on GABAA and glycine receptors (13). We have previously reported pre- and postsynaptic actions of volatile anesthetics on glycinergic transmission to spinal cord motor neurons, which include opposing facilitatory and inhibitory actions on transmitter release and a prolongation of currents postsynaptically with no change in amplitude (14). The present study was performed to compare anesthetic actions on glutamate neurotransmission with those on glycinergic transmission, and to test the hypothesis that volatile anesthetics shift the balance between excitation and inhibition toward inhibition by exerting greater depressant actions on excitatory transmission than on inhibitory. Enflurane was chosen as the anesthetic to make the comparison because, in the previous study, only enflurane significantly depressed the total charge transfer associated with spontaneous glycinergic inhibitory postsynaptic currents (sIPSCs) (14). Enflurane thus provides the most stringent test of the hypothesis. As in the previous study, patch-clamp techniques were used to examine miniature excitatory postsynaptic currents (mEPSCs), spontaneous excitatory postsynaptic currents (sEPSCs), and currents evoked by brief pulses of excitatory neurotransmitter.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Summary
 References
 
Spinal Cord Preparation
Spinal cord slices from 6- to 14-day-old Sprague-Dawley rats were prepared as previously described (13–16). In a protocol approved by Stanford’s panel on laboratory animal care and use, the animals were anesthetized with halothane, decapitated, and spinal cords quickly removed and placed in cold oxygenated artificial cerebrospinal fluid (ACSF). The ACSF was composed as follows (mM): NaCl 123, KCl 4, NaH2PO4 1.2, MgSO4 1.3, NaHCO3 26, D-glucose 10, and CaCl2 2. Slices 350-µm thick were sectioned from the lumbar region on a Vibratome (Technical Products International, Inc., St. Louis, MO), and removed to oxygenated ACSF at room temperature for a 1-h recovery period. Individual slices were transferred to a recording chamber constantly superfused with oxygenated ACSF. All experiments were performed at room temperature.

Whole-Cell Recordings
Whole-cell patch-clamp recordings were made from visually identified motor neurons in the spinal cord slice by using infrared differential interference contrast-videomicroscopy as previously described (13). The largest multipolar or round cells (15–25 µm in diameter) in the ventral horn, most often seen in the ventral lateral or ventral medial area, were identified as motor neurons. Patch pipettes were pulled on a Flaming-Brown pipette puller (Sutter Instruments, Novato, CA) and filled with a solution of the following composition (mM): CsCl 120, NaCl 10, HEPES 10, MgCl2 2, EGTA 10, CaCl2 1, MgATP 4, TEA-Cl 10, pH adjusted with CsOH to 7.3. Pipettes typically had a tip resistance of 2–8 M{Omega}. The patch pipette was directed toward a motor neuron cell body under visual control. After establishment of a Gigohm seal, the patch was ruptured by brief negative pressure and subsequent measurements were made in the whole cell ruptured patch configuration in voltage clamp mode by using an Axopatch 200B patch-clamp amplifier (Axon Instruments, Foster City, CA). Series resistance of 10–15 M{Omega} was compensated by 60%. All cells accepted for data analysis displayed stable resistance values throughout the experiment. Capacitance was also compensated. Holding potential was -60 mV. The membrane potential value was not corrected for junction potential, which was -13 mV. mEPSCs were recorded in the presence of tetrodotoxin (TTX, 0.3 µM) in the bath solution to block Na+-dependent action potentials. sEPSCs were recorded without TTX. To ascertain postsynaptic effects on glutamate receptors, responses were evoked by direct pressure application of glutamate or {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (Picospritzer; General Valve Division of Parker Hannefin Corp., Fairfield, NJ) from a pipette positioned near the cell body. Pressure pulse was 10 PSI; the duration of the pulse was 200 ms. Glutamate concentration in the pipette was 1 mM and AMPA concentration was 200 µM. Glutamate or AMPA applications at 1-min intervals produced stable inward currents over the course of each experiment. AMPA currents were pharmacologically isolated by blocking excitatory N-methyl-D-aspartate (NMDA) and inhibitory GABAA and glycine receptors with D,L-2-amino-5-phosphonopentanoic acid (AP-5) (50 µM), bicuculline (10 µM), and strychnine 1 µM, respectively.

Experiments were performed on a single cell in each slice. A software package (pClamp version 8; Axon Instruments) was used to acquire data. The spontaneous synaptic currents were digitized at 5 kHz, stored in a computer, and analyzed off-line by using Mini Analysis Program 4.3 (Synaptosoft Inc., Decatur, GA). The amplitude threshold for detection of spontaneous miniature synaptic currents was set above the noise level and events were subsequently verified visually. The analysis of mEPSC and sEPSC properties included: frequency, mean peak amplitude, 10%–90% rise time, and decay time constant ({tau}decay). Decay time constants were obtained by fitting from averaged events without overlapping.

Pharmacologic agents were made up as stock solutions, dissolved in ACSF at the desired concentration, and applied in the superfusate. Anesthetic actions were examined at the concentrations associated with abolition of movement in 50% of subjects (MAC), 0.6 mM for enflurane. The concentrations of volatile anesthetics in the bath chamber were measured by using gas chromatography. Volatile anesthetics were applied for 15 min. For analysis of anesthetic effects on sEPSCs and mEPSCs, the controls were events in the 5 min immediately before the start of anesthetic application. Volatile anesthetic effects on mEPSC and sEPSC frequencies were measured over the entire period of application. Effects on kinetic properties and on total charge transfer were measured over the last 5 min of drug application. All anesthetic actions were reversible on washing. Effects were expressed as mean ± SEM. Statistical significance of anesthetic effects was assessed by using Student’s t-test for paired data.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Summary
 References
 
AMPA Receptors
Attention was focused on AMPA receptor-mediated currents for two reasons: in separate studies, we showed that when AMPA and NMDA receptors are blocked by selective antagonists, at most 3% of glutamate-evoked current in motor neurons remains carried by kainate receptors (Knape and Kendig, unpublished data). In the present studies, preliminary observations established that the frequency of spontaneous miniature NMDA receptor-mediated EPSCs is very small. In some cells, spontaneous NMDA currents are seen only when potassium levels are increased or when magnesium is decreased.

The AMPA mEPSC Versus sEPSC
The mean frequency of sEPSCs when sodium channels were not blocked by TTX was 1.55 ± 0.41 s-1 (mean ± SEM, n = 9). The mean amplitude was 22.5 ± 4.8 pA. TTX (0.3 µM) did not significantly alter either frequency or amplitude; mEPSC frequency was 1.49 ± 0.40 s-1 and amplitude 21.5 ± 2.2 pA (n = 10).

Enflurane Decreases Both mEPSC and sEPSC Frequency
Enflurane (0.6 mM) significantly decreased the frequencies of both mEPSCs in the presence of TTX (Fig. 1A) and of sEPSCs when TTX was not present (Fig. 1B). The extent of mEPSC and sEPSC depression was not significantly different. The effects of enflurane are presented graphically for actual frequencies in Figure 2 and as percent of control in Table 1.



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  		Figure 1. Enflurane increased the frequency of miniature excitatory postsynaptic current (mEPSC) both in the presence of tetrodotoxin (TTX) (mEPSCs) (A) and with no TTX present (spontaneous excitatory postsynaptic currents [sEPSCs]) (B). Traces show currents before and during enflurane application (0.6 mM). Graphs to the right of each set of traces show the time course of the frequency changes during and after anesthetic exposure in the same neurons. MAC = minimum alveolar anesthetic concentration. Bin width = 10 s.

 


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  		Figure 2. Enflurane actions on miniature excitatory postsynaptic current (mEPSC) (n = 10) and spontaneous excitatory postsynaptic current (sEPSC) (n = 9) frequency. Error bars are SEM. *, **Significantly different from control, P < 0.05 and P < 0.01, respectively.

 

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  		Table 1. Effects of the Volatile Anesthetic Enflurane at 0.6 mM (1 MAC) on Normalized Frequency, Mean Peak Amplitude, and Total Negative Charge Transfer of Non N-methyl-D-aspartate (NMDA) mEPSCs and sEPSCs
 
Enflurane Has No Effect on mEPSC or sEPSC Amplitude or Kinetics but Significantly Reduces Total Charge Transfer
Enflurane did not alter amplitude, rise time, or Tdecay of either mEPSCs or sEPSCs (Tables 1 and 2). The combination of decreased frequency and unchanged amplitude and duration resulted in a decrease in total charge transfer for both mEPSCs and sEPSCs; the extent of the decrease was not different.


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  		Table 2. Effects of Enflurane at a Concentration of 0.6 mM (1 MAC) on Amplitude, 10%–90% Rise Time, and {tau}decay of non N-methyl-D-aspartate (NMDA) mEPSCs and sEPSCs
 
Enflurane Effects on AMPA-Evoked Currents
To isolate postsynaptic enflurane actions, we investigated currents evoked by pressure ejection of AMPA. Enflurane 0.6 mM significantly decreased both amplitude and area of AMPA-evoked currents but did not significantly change decay time (Fig. 3). The results were reversible on washing. In some, but not all cells, the response recovered to a level above control as seen in the example in Figure 3A. Because of this, enflurane effects were tabulated using as control an average of the pre- and post-enflurane values (Table 3). Some neurons also showed an acute tolerance to the effects of enflurane, depression at 5 min being larger than that observed at the end of the period of application at which measurements were made.



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  		Figure 3. Enflurane actions on {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-evoked currents. A, An example showing reversible depression by enflurane; currents in this cell recovered to a level slightly above control. B, Enflurane significantly decreased amplitude and area of the evoked currents but had no effect on decay time. Error bars are SEM. *, **P < 0.05 and 0.01, respectively.

 

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  		Table 3. Enflurane Actions on {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)-Evoked Currents; Amplitude, Area, and Decay Time
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Summary
 References
 
Properties of AMPA-Mediated mEPSCs and sIPSCs Compared with Glycinergic Inhibitory Currents
In our previous study, block of sodium channels by TTX significantly depressed the frequency and amplitude of spontaneous events, i.e., glycinergic mIPSC frequency and amplitude were much lower than for sIPSCs. In contrast, there was no difference between AMPA-mediated mEPSC and sEPSC frequency or amplitude. Thus, spontaneous glutamate transmitter release to motor neurons is not dependent on sodium channels, whereas glycine release is. In this glutamate release to motor neurons resembles GABA release to hippocampal interneurons, in which sodium channel block also had little effect (17,18). It should be emphasized, however, that the events recorded in the present study as in others are predominantly attributed to receptors on or close to the cell body, with little contribution from dendritic synaptic sites.

Presynaptic Actions of Enflurane
Frequency of spontaneous transmitter release is determined presynaptically, amplitude and kinetics postsynaptically. Enflurane significantly depressed both mEPSC and sEPSC frequency to the same extent, and decreased total charge transfer for both. Just as glutamate release itself does not seem to be dependent on sodium channels, enflurane actions are similarly unaffected by sodium channel block. In contrast, enflurane actions on glycine release are strongly dependent on sodium channels; a significant increase in mIPSC frequency is converted to a significant decrease in sIPSC frequency when sodium channels are intact (14). The fundamental mechanisms of transmitter release are revealed when sodium channels are blocked. Enflurane thus exerts opposite effects on the fundamental mechanisms of glutamate and glycine release, decreasing one and increasing the other. Sodium channel block, however, is an artificial condition. Under the more natural condition of intact sodium channels, enflurane decreases both sEPSC and sIPSC frequencies to approximately the same extent. This finding was not predicted by the hypothesis, which envisioned a greater sEPSC than sIPSC frequency depression because it is unopposed by facilitation of fundamental glutamate release mechanisms.

Anesthetic reduction of excitatory transmitter release has previously been reported for several preparations, as has involvement of sodium channels in some cases. In spinal cord, ethanol decreases mEPSC and increases mIPSC frequency (19). Sevoflurane reduces 4-aminopyridine-evoked glutamate release from human cortical synaptosomes (20), and an experimental cyclobutane anesthetic reduces potassium-evoked glutamate release from mouse cortical slices (21). In hippocampus, at least some of the depressant effects of halothane on synaptic transmission are attributed to presynaptic actions (5,6). Isoflurane inhibits glutamate release from guinea pig synaptosomes in a manner partially dependent on sodium channels (22). In spinal dorsal horn, halothane reduces both the presynaptic and postsynaptic response to dorsal root stimulation, suggesting that inhibition of primary afferent sodium channels contributes to anesthetic depression (23). Thus, although anesthetic depression of glutamate release seems universal, glutamate release to spinal motor neurons appears to differ from other central nervous system sites both in the dependence of release on sodium channels and consequently in the contribution of sodium channel inhibition to anesthetic action. At motor neurons, glutamate release is not dependent on sodium channels and therefore anesthetic actions on sodium channels do not contribute to depression of release.

Postsynaptic Actions of Enflurane
Enflurane had no significant effects on mEPSC or sEPSC kinetics or amplitude, and no effects on AMPA-evoked kinetics. Enflurane did, however, depress AMPA-evoked current amplitude. This result is in agreement with our previous observation that volatile anesthetics (13) and ethanol (15) directly depress currents evoked by glutamate when NMDA receptors are blocked, leaving the remaining current mediated by AMPA receptors. The discrepancy between currents evoked by endogenous and exogenous transmitter may be attributed to anesthetic depression of presynaptic glutamate receptors. Activation of presynaptic glutamate receptors by exogenous transmitter may contribute to glutamate release by depolarizing presynaptic terminals. If this is the case, then anesthetics may not exert significant postsynaptic actions on AMPA receptors. However, the difference may also be attributed to different receptor populations, those responding to exogenous AMPA possibly being largely extrasynaptic, whereas miniature currents are probably located at synapses.

Although most attention has focused on inhibitory chloride channels as sites of anesthetic action, it is now recognized that volatile and gaseous anesthetics also act on glutamate channels. Isoflurane exerts equal depressant actions on glutamate AMPA and NMDA channels in cultured hippocampal neurons (3). Xenon in contrast has little effect on AMPA currents but does depress NMDA current (3). In Xenopus oocytes, glutamate receptors were inhibited by nitrous oxide, xenon, isoflurane, and ethanol, with NMDA receptors appearing somewhat more sensitive than AMPA (7).

Several studies have examined either presynaptic anesthetic actions on transmitter release or postsynaptic actions on receptors. The present study is innovative in examining both simultaneously, and in comparing excitatory transmission to inhibitory in the same preparation.

Role of Anesthetic Actions on Glutamate Neurotransmission in Anesthesia
The results of the present study are relevant to the anesthetic end point of immobility in response to a noxious stimulus (MAC), because this end point is predominantly determined in spinal cord (9–12). Therefore, with respect to this anesthetic end point, they carry a significance greater than studies at other central nervous system sites or in nonneural cells. In in vivo studies of MAC, GABAA and glycine receptors account for a maximal 40% of the response (24,25). In mice lacking the GluR2 subunit of the AMPA receptor, volatile anesthetic requirement for loss of righting reflex and increase in hindpaw withdrawal latency were decreased, whereas MAC values were unchanged (26). However, as we have previously noted (27), because of developmental compensation, global deletions of an important receptor subunit can lead to unpredicted consequences. Thus, it is difficult to interpret results from genetically engineered animals with respect to the phenomenon of interest.

Like many studies on isolated systems, the present study is a reductionist simplification of a complex system. Other than AMPA currents, all fast currents through glutamate, GABAA, and glycine receptors were blocked. Thus, all potential interactions among receptors were eliminated. The extent to which this may modify anesthetic actions is suggested by a study in which IV anesthetic depression of glutamate release in cortical slice was found to be caused, in part, by actions on GABAA receptors (28).


   Summary
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Summary
References
 
In the present study, we focused on enflurane; it is possible that the results may not apply to other volatile anesthetics without modification. The results show a clear difference between enflurane’s actions on glutamate versus glycine synaptic transmission. Enflurane pre- and postsynaptic actions on glutamate transmission to AMPA receptors are purely inhibitory; glutamate release is decreased under all conditions, and postsynaptic responses are either unchanged or decreased in amplitude with no change in decay time constant. In contrast, enflurane’s actions on glycinergic transmission are in part facilitatory, glycine release being increased in some conditions and postsynaptic responses prolonged. These differences may be sufficient to shift the balance between synaptic excitation and inhibition in the direction of inhibition.


   Acknowledgments
 
Supported by National Institutes of Health Grants NS13108 and GM47818 to JJK.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Summary
 References
 

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Accepted for publication December 26, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press