Anesth Analg 2004;98:1718-1723
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000112309.80017.3F
ANESTHETIC PHARMACOLOGY
Isoflurane Reduces Glutamatergic Transmission in Neurons in the Spinal Cord Superficial Dorsal Horn: Evidence for a Presynaptic Site of an Analgesic Action
Rainer Haseneder*,
Jörge Kurz*,
Hans-Ulrich U. Dodt
,
Eberhard Kochs*,
Walter Zieglgänsberger,
Michaela Scheller*,
Gerhard Rammes, and
Gerhard Hapfelmeier*
*Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, and the
Department of Clinical Neuropharmacology, Max-Planck-Institute of Psychiatry, Munich, Germany
Address correspondence and reprint requests to Rainer Haseneder, Max-Planck-Institute of Psychiatry, Munich, Kraepelinstrasse 2-10, 80804 Munich, Germany. Address email to haseneder{at}mpipsykl mpg.de.
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Abstract
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The minimum alveolar concentration (MAC) of a volatile anesthetic defines anesthetic potency in terms of a suppressed motor response to a noxious stimulus. Therefore, the MAC of an anesthetic might in part reflect depression of motor neuron excitability. In the present study we evaluated the effect of isoflurane (ISO) on neurons in the substantia gelatinosa driven synaptically by putative nociceptive inputs in an in vitro spinal cord preparation of the rat. Whole-cell patch-clamp recordings were performed in neurons with their soma in the substantia gelatinosa of transverse rat spinal cord slices. We investigated the effect of ISO on excitatory postsynaptic currents (EPSC) evoked by dorsal root stimulation (eEPSC), spontaneous (sEPSC), and miniature (mEPSC) EPSC. ISO reversibly reduced the amplitude of eEPSC to 39% ± 22% versus control. ISO decreased the frequency of sEPSC and mEPSC to 39% ± 26% and 63% ± 7%. Neither the amplitudes nor the kinetics of mEPSC and sEPSC were altered by ISO. We conclude that ISO depresses glutamatergic synaptic transmission of putative nociceptive primary-afferent inputs, presumably by reducing the release of the excitatory transmitter. This effect may contribute to an antinociceptive action of volatile anesthetics at the spinal cord level.
IMPLICATIONS: The present electrophysiological in vitro experiments provide evidence that the volatile anesthetic isoflurane reduces excitatory transmitter release at the first site of synaptic integration of nociceptive inputs, the spinal cord superficial dorsal horn. This effect may contribute to the anesthetic action of volatile anesthetics at the spinal cord level.
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Introduction
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The minimum alveolar concentration (MAC) of a volatile anesthetic prevents movement in response to a defined noxious stimulus in 50% of subjects and determines the drug’s anesthetic potency (1). Several previous studies have shown that the spinal cord is one of the most important sites of action for volatile anesthetics in the suppression of motor responses to noxious stimuli (2–4). At the spinal cord level, this effect might result from either suppression of neuronal activity in the ventral horn (e.g., motor neuron excitability) or reduced sensory transmission of nociceptive signals within the dorsal horn (5). Many of the previous studies investigating the effect of volatile anesthetics on spinal cord motor neurons showed depression of motor neuron excitability (3,6) or synaptic activation (7–10)—effects thought to contribute to the immobilizing property. There is, however, little information as to how volatile anesthetics affect synaptic transmission in neurons of the spinal cord dorsal horn.
Nociceptive signals transmitted by thin- (A
-) and unmyelinated (C-) primary afferent fibers are conveyed to neurons in the superficial laminae (substantia gelatinosa, SG) of the spinal cord dorsal horn as the first site of their synaptic integration (11,12). Thus, inhibition of SG neuron activity might provide a key mechanism of antinociception (13). Therefore, in the present study we evaluated the effect of isoflurane (ISO) on the synaptic transmission of putative nociceptive inputs to SG neurons, using an in vitro slice preparation of rat spinal cord.
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Methods
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The experimental protocols were approved by the Ethics Committee on Animal Care and Use of the Government of Bavaria, Germany. After administration of oxygenation, 12 to 20 day old Wistar rats of either sex were deeply anesthesized with ISO (ForeneTM, Deutsche Abbott GmbH, Wiesbaden, Germany). During the preparation, the head of the anesthesized rat was held in a tube (diameter, 28 mm) delivering a continuous flow of oxygen supplemented with ISO as required. The lumbar spinal cord was removed after laminectomy, with long (8–12 mm) dorsal roots attached. Throughout the dissection, the cord was continuously superfused with ice-cold artificial cerebrospinal fluid (aCSF) containing (in mM) NaCl 125, KCl 2.5, NaHCO3 25, CaCl2 2, MgCl2 1, D-glucose 25, NaH2PO4 1.25, pH 7.4, bubbled with a 95% O2/5% CO2 mixture. The lumbar spinal cord was then transferred into a dish containing ice-cold, oxygenated aCSF, and freed from remnants of dura mater. Ventral roots of both sides and dorsal roots of one side were cut under an operating microscope (Wild, Heerbrugg, Germany). A vibroslicer (FTB, Villingen, Germany) was used to cut several transverse slices (400–500 µm thick) from segments L4-S1 with an intact dorsal root attached. All slices were incubated at least for 1 h in oxygenated aCSF at room temperature.
Slices were transferred to a superfused chamber (Luigs & Neumann, Ratingen, Germany) to record stimulus-evoked (eEPSC), spontaneous (sEPSC), or miniature excitatory postsynaptic currents (mEPSC) from SG neurons. The flow rate of oxygenated aCSF through the chamber was 1.5 mL/min. A platinum grid with nylon filaments was used to fix the slice on the bottom of the recording chamber. The dorsal root was carefully aspirated into a suction electrode for stimulation of the primary afferent nerve fibers. The SG was clearly identifiable as a translucent band across the dorsal horn (Fig. 1 A). We used infrared gradient contrast videomicroscopy (14) to visualize the somata of SG neurons (Fig. 1 B), from which whole-cell patch-clamp recordings were performed.
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Figure 1. A, image of a transverse lumbar spinal cord slice with one dorsal root (DR) attached. The distal part of the DR was sucked into a suction electrode (SE). A platinum ring with nylon filaments (NF) fixed the slice at the bottom of the recording chamber. The substantia gelatinosa (SG) is clearly visible as a translucent band in the dorsal part of the spinal cord (dashed area). B, SG neuron, visualized by infrared gradient contrast videomicroscopy.
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The patch pipettes were pulled from thin-walled borosilicate glass tubes with inner filament (outer diameter, 1.5 mm; inner diameter, 1.17 mm; GC150TF-10; Clark Electromedical Instruments, Pangbourne Reading, UK) and heat polished using a two-step horizontal puller (DMZ-Universal Puller, Zeitz-Instruments, Munich, Germany). Pipettes had a series resistance of 4–6 M
, when filled with a solution containing (in mM) K-D-gluconate 130, KCl 5, EGTA 0.5, MgCl2 2, HEPES 10, D-glucose 5, Na2-phosphocreatine 20. Currents were recorded with a switched voltage-clamp amplifier (SEC 10L; NPI electronic, Tamm, Germany) with switching frequencies of 60–80 kHz (25% duty cycle). Series resistance was monitored continuously and compensated in bridge mode. All patch-clamp experiments were performed at room temperature (22°C–25°C) at a holding potential of –70 mV.
SG neurons were activated synaptically by electrical stimulation of primary afferent fibers in the dorsal roots via a suction electrode. We used a stimulation interval of 60 s, which did not result in response facilitation or depression. The stimulus intensity was adjusted to yield eEPSC with amplitudes between 100 and 200 pA.
mEPSC were recorded in the presence and sEPSC in the absence of 1 µM tetrodotoxin (TTX) from neurons that also yielded current responses on dorsal root stimulation.
The whole-cell responses were amplified, low-pass filtered (3 kHz), and then digitized (ITC-16 Computer Interface; Instrutech Corp., Port Washington, NY) with a sampling frequency of 9 kHz and stored on a hard disk (Power Macintosh G3 computer; Apple, Cupertino, CA; data acquisition software Pulse v. 8.31; Heka electronic GmbH, Lambrecht, Germany). The data obtained were analyzed with IGOR Pro software (WaveMetrics, Lake Oswego, OR).
For detection of mEPSC and sEPSC, the amplitude threshold was defined as the threefold amplitude of the baseline variance (noise level), and the events identified were subsequently verified visually. We quantified the frequency, peak amplitudes, 10%–90% rise times, and decay times of the mEPSC and sEPSC signals.
Numerical data are presented as means ± SEM with the number of experiments indicated if not stated otherwise. Data were analyzed using Student’s t-test. A value of P < 0.05 was considered statistically significant.
Drugs were applied by superfusing the slices with solutions of known drug concentrations. A single ISO concentration of 0.3 mM (approximately 1 MAC equivalent) (15) was used throughout the study. Application of ISO was accomplished as described previously (16). Briefly, ISO was added to the superfusate by diluting a stock solution of ISO (15 mM). The concentration of the anesthetic in the recording chamber was measured by gas chromatography. In this series of experiments, one representative measurement of the ISO concentration in the recording chamber revealed a value of 0.32 mM. The addition of ISO did not change the pH of the superfusate. TTX and 2,3-dihydroxy-6-nitro-7-sulfoamyl- benzo(F)-qinoxaline (NBQX) (both Sigma, Deisenhofen, Germany) were applied by adding aliquots of known concentrations to the superfusate.
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Results
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The SG neurons showed a mean resting membrane potential of –60.6 ± 3.2 mV and a mean input resistance of 297 ± 38 M. Neither resting membrane potential nor input resistance changed significantly when superfused with ISO.
Stimulation of afferent fibers within the dorsal root evoked postsynaptic responses (eEPSC) in the neurons. When no lack of responses occurred under repetitive stimulation at a frequency of 10 Hz, the eEPSC were considered to be induced monosynaptically because not every stimulus (at 10 Hz) can evoke a polysynaptically EPSC (12). The quotient of eEPSC latency and the length of the dorsal root revealed the conduction velocities of the afferent fibers, ranging from 0.25 and 3.2 m/s (with central delay considered as to be 1 ms). Thus, the eEPSC were considered to be driven by A- or C-afferent fibers.
The eEPSC had a mean amplitude of 150 ± 32 pA. eEPSC, sEPSC, and mEPSC were blocked by the AMPA/kainate receptor antagonist NBQX (5 µM; data not shown).
After recording 20 control eEPSC (interval of 60 s), ISO (1 MAC) was added to the superfusate. ISO reversibly reduced the eEPSC amplitude in all neurons tested. Figure 2 A shows eEPSC recordings from two representative experiments. Figure 2 B depicts data pooled from 8 experiments (*P < 0.05). The eEPSC latency (stimulation artifact to eEPSC onset) was used to estimate the conduction velocity of the afferent fiber activating the neuron under study (Fig. 2 C). ISO did not affect the eEPSC latencies (Fig. 2C, open circles).
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Figure 2. Effect of isoflurane (ISO, 0.3 mM = 1 MAC equivalent) on evoked excitatory postsynaptic currents (eEPSC) recorded from substantia gelatinosa (SG) neurons. eEPSC were evoked by stimulation of afferent fibers in the dorsal root via a suction electrode. A stimulation interval of 60 s was used. A, current traces recorded from two SG neurons, displaying different latencies between stimulation and eEPSC onset ( stimulation artifact truncated for illustrative purposes). ISO reversibly reduced the eEPSC. B, normalized data from 8 experiments. In all SG neurons tested, superfusion of the spinal cord slice with artificial cerebrospinal fluid (aCSF) containing ISO (0.3 mM) resulted in a reduction of the eEPSC amplitude (*P < 0.05). Error bars are SD. MAC = minimum alveolar anesthetic concentration. C, distribution of conduction velocities (quotient of dorsal root length and latency) of the investigated neurons. When no failures of responses occurred under repetitive stimulation at a frequency of 10 Hz, the eEPSC were considered to be induced monosynaptically. The experiments depicted in A are assigned with # and ##.
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sEPSC recorded from SG neurons occurred at a frequency of 3.8 ± 3.1 Hz and had a mean amplitude of 18 ± 5.2 pA. Superfusion with ISO (1 MAC) reduced the sEPSC frequency (Fig. 3 A). Figure 3 B shows the effect of ISO on cumulative distributions of sEPSC inter-event intervals and amplitudes. ISO increased the proportion of sEPSC having a longer inter-event interval and had no effect on the distribution of the amplitudes. Figure 3 C shows pooled data: ISO reduced the sEPSC frequency to 39% ± 26% (n = 5, P < 0.05), whereas the amplitudes remained unchanged (18 ± 4.0 pA, n = 5). Rise time and decay time (
decay) of the sEPSC were not altered by ISO (Table 1).
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Figure 3. Isoflurane (ISO) reduced the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSC) recorded from substantia gelatinosa (SG) neurons at a holding potential of –70 mV. A, traces of sEPSC recordings under control conditions, under delivery of ISO, and after washout of ISO. B, cumulative distributions resulting from one representative experiment. ISO notably increased the intervals between sEPSC events but had no discernible effect on their amplitudes. C, pooled data from five experiments. Error bars are SEM; *significantly different (P < 0.05) from control. MAC = minimum alveolar anesthetic concentration.
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Table 1. Rise Time and Time Constant of Decay of Miniature Excitatory Postsynaptic Currents and Spontaneous Excitatory Postsynaptic Currents
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mEPSC were recorded in the presence of TTX (1 µM). The frequency was 1.5 ± 0.4 Hz with a mean amplitude of 8.8 ± 2.3 pA. ISO reduced the mEPSC frequency (Fig. 4 A), as indicated also by the rightward shift of the inter-event interval distribution (Fig. 4 B left). The distribution of the mEPSC amplitudes remained unaffected (Fig. 4 B right). On average, ISO reduced the mEPSC frequency to 63% ± 7% (n = 7, P < 0.01, Fig. 4 C). Amplitude (8.7 ± 3.2 pA, n = 7, Fig. 4 C), rise time, and decay time of the mEPSC were not altered by ISO (Table 1).
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Figure 4. Isoflurane (ISO) reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSC) recorded from substantia gelatinosa (SG) neurons. mEPSC were recorded in the presence of 1 µM tetrodotoxin at a holding potential of –70 mV. A, traces of mEPSC recorded from a SG neuron before, during, and after superfusion of the spinal cord slice with ISO. B, cumulative distributions of inter-event intervals and amplitudes from one representative experiment. ISO shifted the distribution of intervals between mEPSC events to longer intervals but had no discernible effect on the distribution of the amplitudes. C, pooled data from seven experiments. Error bars are SEM; **significantly different (P < 0.01) from control. MAC = minimum alveolar anesthetic concentration.
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Discussion
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Our study demonstrates that the volatile anesthetic, ISO, reduces glutamatergic synaptic transmission of putative nociceptive inputs to spinal cord SG neurons in a slice preparation of the rat. This is the first report on the effect of volatile anesthetics on postsynaptic currents in dorsal horn neurons recorded intracellularly.
A previous approach to evaluate in vitro nociceptive neurotransmission in the spinal cord was the measurement of slow ventral root potentials, which were suppressed by volatile anesthetics (17). These potentials meet several criteria for a nociceptive response even though they are generated in motor neurons and underlie modulations of neuronal activity within the ventral horn. Therefore, in the present work, we recorded postsynaptic responses in dorsal horn neurons to evaluate the effect of ISO at the first site of synaptic integration of nociceptive inputs.
We demonstrated that ISO decreased the frequency of glutamatergic mEPSC/sEPSC recorded from spinal cord SG neurons. Such miniature synaptic currents reflect quantal transmitter release (18). Therefore, the ISO-induced suppression of synaptic transmission in these neurons might result from a reduced synaptic glutamate release. Under our experimental conditions, mEPSC/sEPSC amplitudes and kinetics remained unaffected. This indicates that ISO did not substantially interact with postsynaptic glutamate receptors. Our findings are in line with a recent work using an optical imaging technique that showed that halothane suppressed neuronal C-fiber-evoked excitation in superficial dorsal horn via a presynaptic mechanism (19).
L-Glutamate, released from primary afferents and activating AMPA receptors, is the major excitatory neurotransmitter conveying nociceptive signals to dorsal horn neurons (20). An inhibition of glutamatergic neurotransmission in the spinal cord has antinociceptive effects in various animal pain models (21,22). Inhibition of glutamatergic synaptic transmission in the spinal cord dorsal horn is also an important mechanism of the analgesic action of opioid peptides: several studies suggest that opioid antinociceptive action is, at least in part, mediated via a reduction of excitatory transmitter release from dorsal horn terminals of primary afferents (23,24). Cannabinoids mediate a presynaptic inhibition of the excitatory synaptic transmission in the SG, an effect that is thought to contribute to an analgesic action (25).
The reduced glutamate release in the spinal cord dorsal horn, as shown in our study, might contribute to an antinociceptive effect of ISO. Our results also explain the previous finding that volatile anesthetics depress the firing rate in dorsal horn neurons on a noxious stimulus (26,27).
Most patch-clamp studies, investigating the action of volatile anesthetics on spinal cord level, focused on motor neurons. Several volatile anesthetics reduce motor neuron excitability (3,6). Halothane depresses synaptic transmission in spinal motor neurons (7). More recent studies have shown that volatile anesthetics enhance the glycinergic synaptic inhibition and depress the glutamatergic excitation in spinal cord motor neurons (10,28). These actions may contribute to the state of anesthesia when viewed from the end-point of the production of immobility. However, a decreased motor neuron excitation does not contribute to analgesia and the loss of consciousness.
In summary, clinically relevant concentrations of the volatile anesthetic ISO can depress synaptic transmission at the first site of synaptic integration of nociceptive inputs, the spinal cord superficial dorsal horn, mainly via a presynaptic mechanism. This effect might contribute to an analgesic action and, by diminishing the strength of arousing stimuli, to loss of consciousness. Therefore, this effect might be involved in pain prevention during anesthesia.
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Acknowledgments
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Supported, in part, by a grant of the Deutsche Forschungsgemeinschaft (Sche 626[1-4]).
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Accepted for publication November 26, 2003.
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Abstract
Introduction
