Department of Cellular and Molecular Pharmacology, Discovery Division, Astra Pain Control AB, S-141 57 Huddinge, Sweden
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ABSTRACT |
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Sequeira, Sandra and Jacques Näsström. Low-affinity kainate receptors and long-lasting depression of NMDA-receptor-mediated currents in rat superficial dorsal horn. J. Neurophysiol. 80: 895-902, 1998. In an in vitro spinal cord slice preparation whole cell electrophysiological recordings of rat superficial dorsal horn neurons responding differentially to glutamate (Glu) and N-methyl-D-aspartate (NMDA) were investigated systematically for the role of kainate (KA) receptors in modulating their activity. In these neurons, coapplication of Glu and NMDA, as well as application of Glu immediately before NMDA, induced long- and short-lasting depressions of NMDA-induced currents as well as depression of NMDA-receptor-mediated excitatory postsynaptic currents. KA applied before NMDA mimicked Glu-induced attenuating effects. Furthermore, the low-affinity KA receptor antagonist 5-nitro-6,7,8,9- tetrahydrobenzo[G]indole-2,3-dione-3-oxime potentiated Glu-induced NMDA-receptor-mediated currents in neurons responding differentially to Glu and NMDA. These results provide evidence for a novel mechanism, which may relate to classical long-term depression, involving low-affinity KA receptors in long-lasting modulation of NMDA-receptor-mediated currents. This implies a physiological role of KA receptors in long-term modulation of sensory transmission in the superficial dorsal horn of rat spinal cord.
The superficial dorsal horn, which includes the substantia gelatinosa (SG), is an area important for reception and processing of primary afferent information on pain and other sensory modalities conveyed by slowly conducting fibers (Cervero and Iggo 1980 Tissue preparation
The method employed for slice preparation of the rat spinal cord was modified from that described by Yoshimura and Nishi (1993) Whole cell patch-clamp recordings
Whole cell patch-clamp recordings were made from SG neurons. Through a dissecting microscope, the SG was identified as a distinct relatively translucent band across the dorsal horn. Patch pipettes (5-8 M Dorsal root stimulation
Afferent volleys of action potentials were initiated by constant-current stimuli (30-600 µA, 300 µs, 0.1 Hz) delivered to the dorsal root with a suction electrode. Neurons were classified according to their dorsal root input, based on stimulus intensities and conduction velocities, as described earlier (Näsström et al. 1994 Drugs and solutions
The following drugs were used: tetrodotoxin (TTX; 1 µM; sodium channel blocker), (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten,10 imine (MK-801; 50 µM; noncompetitive NMDA receptor antagonist) (Wong et al. 1986 Calculations and statistics
NMDA- and Glu-induced currents were normalized to the maximal NMDA-induced current for each cell. Normalized values were expressed as a percent of the maximal NMDA-induced current and were subsequently used to generate dose-response curves. Dose-response curves were obtained by plotting the mean ± SE values of the normalized currents against concentration. Any values deviating >2 SD from the mean were excluded from dose-response curves. On this basis, responses from one neuron were excluded. Dose-response curves were generated by fitting the data, by nonlinear regression, to the following equation
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Christensen and Perl 1970
; Kumazawa and Perl 1978
). Excitatory synaptic transmission, relayed from A
and C fiber afferents to dorsal horn neurons, is mediated primarily by the excitatory amino acid (EAA) L-glutamate (Glu) acting at glutamate receptors (for reviews, see Marmo 1988
; Watkins and Evans 1981
). More recent studies have indicated that glutamate receptors of both N-methyl-D-aspartate (NMDA) and non-NMDA types also may underlie modulation of excitatory transmission, including long-term depression (LTD) (for reviews, see Asztely and Gustafsson 1996
; Linden and Connor 1995
).
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type are expressed on many neurons of the spinal cord with the highest density of binding sites being found in the superficial dorsal horn (Aanonsen and Seybold 1989
; Jakowec et al. 1995
; Monaghan and Cotman 1985
; Tölle et al. 1993
). Kainate (KA) receptors encoding the low-affinity binding sites (GluR5-GluR7) (Bettler and Mulle 1995
) are also abundant in the superficial dorsal horn (Bonnot et al. 1996
; Tölle et al. 1993
), however, in contrast to NMDA and AMPA receptors, the role of KA receptors in synaptic function remains largely unknown (for reviews, see Bettler and Mulle 1995
; Lerma et al. 1997
).
) that was suggested to result from action at presynaptic low-affinity KA receptors. Although this is a possibility, the mechanisms underlying such synaptic depression have yet to be fully elucidated.
; Schneider and Perl 1985
, 1988
; Yajiri et al. 1997
; Yoshimura and Jessell 1990
). Furthermore, neurons in this region possess differential sensitivities to NMDA and Glu (Näsström et al. 1994
). We undertook to investigate the cellular mechanisms possibly underlying this differential responsiveness, paying attention to the part of KA receptors and physiological characteristics of those neurons exhibiting it.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
. Briefly, 3- to 5-wk-old male Sprague-Dawley rats (B&K Universal AB, Sollentuna, Sweden) weight 80 ± 3 g (mean ± SE); ranging from 46 to 175 g (n = 134) were anesthetized with urethan (1.5 g/kg ip) and then cooled on ice to a rectal temperature below 30°C. A lumbosacral laminectomy was performed, the lumbrosacral spinal cord (L1-S1) with attached ventral and dorsal roots removed and quickly placed in ice-cold, preoxygenated (95% O2-5% CO2), modified artificial cerebrospinal fluid (mACSF) with the following composition (in mM): 225 sucrose, 5 KCl, 1.25 NaH2PO4, 22 NaHCO3, 2.5 CaCl2, 1.5 MgSO4, and 10 D-glucose. The pH and osmolarity of the mACSF were ~7.3 and 325-335 mOsm, respectively. After removing the pia-arachnoid meninges, all spinal roots were removed near their entry zone, except for the L4 to L6 dorsal roots on one side. Transverse slices 700-900 µm thick with dorsal roots attached were cut with a vibratome (Vibratome 1000, Ted Pella, Redding, CA). A slice was placed in the recording chamber (volume 1.1 ml) in which it was supported mechanically by a grid of parallel nylon threads (Edwards et al. 1989
) and superfused (10 ml/min) with preoxygenated 25-27°C Mg2+-free ACSF with the following composition (in mM): 120 NaCl, 5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 2.5 CaCl2, and 10 D-glucose. The pH and osmolarity of the ACSF were ~7.4 and 300-310 mOsm, respectively.
) were pulled from borosilicate glass (No. 7052, A-M Systems, Everett, WA), and pipette tips were coated with Sigmacote and filled with internal solution of the following composition (in mM): 130 K-gluconate, 11 ethylene glycol-bis(
-aminoethyl ether)-N,N,N',N'-tetraacetic acid, 5 NaCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 2-4 Mg-ATP, 0.2 Li-GTP, and 0.005 phalloidin; osmolarity was 290-300 mOsm, pH was adjusted to 7.2 using KOH. The liquid junction potential was measured at ~9 mV by the method described by Neher (1992)
and has been subtracted from all potential values given. Gigaohm seals of SG neurons were achieved using the blind technique, i.e., by monitoring current flow through the pipette on an oscilloscope while lowering the pipette onto a cell. Whole cell recordings were performed in voltage clamp mode at a holding potential of
69 mV using a standard patch clamp amplifier (Axopatch 200A, Axon Instruments, Foster City, CA). Data were digitized and stored on video tape and computer disk for subsequent analyses. Only neurons with a resting membrane potential more negative than
50 mV that displayed sodium currents after voltage steps (
99 to
9 mV; 10 ms duration; 10 mV increments) were selected for further recording.
). Briefly, intensities between 30 and 60 µA evoked short latency synaptic responses corresponding to a conduction velocity of ~2-4 m/s (A
fibers), higher intensity stimulations (120-300 µA) evoked longer latency responses in a subset of the neurons corresponding to a conduction velocity of <1 m/s (C fiber).
), 5-nitro-6,7,8,9- tetrahydrobenzo[G]indole-2,3-dione-3-oxime (NS-102; 10 µM; low-affinity KA receptor antagonist) (Johansen et al. 1993
; Verdoorn et al. 1994
) all obtained from Research Biochemicals International (Natick, MA). 6-Nitro-7-sulfomoylbenzo[f]-quinoxaline-2,3-dione (NBQX; 10 µM; competitive non-NMDA receptor antagonist) (Sheardown et al. 1990
), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 200 µM; metabotropic glutamate receptor agonist), and KA (100 µM) were obtained from Tocris Cookson (Langford Bristol, UK). L-Glutamate (Glu), NMDA, phalloidin (5 µM; actin filament depolymerization inhibitor) (Rosenmund and Westbrook 1993
), and Sigmacote were obtained from Sigma Chemical (St. Louis, MO).
10 min before agonist application. The agonists Glu and NMDA were superfused (30 s) in alternating order, unless otherwise indicated. Agonist induced responses were studied in Mg2+-free ACSF containing 1 µM TTX and 10 µM NBQX.
where [D] represents the drug concentration, EC50 represents the concentration that produces half-maximal effect, and z determines the slope and curvature. When appropriate, data were statistically analyzed by
2 test, Mann-Whitney U test, paired t-test, repeated measure analysis of variance (ANOVA) followed by Newman-Keuls post hoc test or Wilcoxon matched-pairs test, using Statistica version 5.0.
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RESULTS |
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General characteristics of the sampled dorsal horn neurons
Stable tight-seal whole cell recordings were obtained from 137 superficial dorsal horn neurons, the visually located recording sites of which are illustrated in Fig. 1 (see figure legend for details). The average resting membrane potential was 69 ± 0.3 (SE) mV (n = 134); ranging from
54 to
74 mV and the mean input resistance was 359 ± 17 M
(n = 137); ranging from 120 to 1,000 M
. These results are comparable with previous reports on dorsal horn neurons using similar recording techniques (Miller and Woolf 1996
; Yajiri et al. 1997
). Postsynaptic currents evoked by dorsal root stimulation were obtained from 107 neurons. Excitatory postsynaptic currents (EPSCs) were evoked in the majority of these neurons. On the basis of stimulus intensity and conduction velocity, a neuron was labeled A only if EPSCs were associated with activity in myelinated A
fibers (30-60 µA, 2-4 m/s). Neurons with EPSCs associated with activity in C fibers only, were classified as C only (120-300 µA, <1 m/s). Neurons with EPSCs associated with activity in myelinated A fibers and unmyelinated C fibers were classified as A + C. Based on these criteria, 73% (73/100) of the neurons were classified as A only, 11% (11/100) were classified as C only and 16% (16/100) were classified as A + C. Inhibitory postsynaptic currents (IPSCs) were evoked by dorsal root stimulation in 17% (18/107) of the neurons.
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Inward currents induced by Glu and NMDA
Given diffusion and inactivation considerations (see DISCUSSION), 12 mM Glu represents a relevant physiological concentration. Bath applications of 12 mM Glu induced inward currents of 358 ± 39 pA; ranging from 20 to 1,806 pA, in nearly all 105/110 (95%) of the neurons tested. The average duration of Glu-induced currents at 50% of peak inward current was 26 ± 1 s (n = 47). Bath application of NMDA (100 µM) induced inward currents of 828 ± 67 pA; ranging from 60 to 3,632 pA, in 112/116 (97%) of the neurons tested. The average duration of NMDA-induced currents at 50% of peak inward current was 73 ± 2 s (n = 47). In about one-half the cells, NMDA-receptor-mediated currents induced by Glu were significantly smaller in peak amplitude than those induced by NMDA (Fig. 2A). A comparison of a number of neurons at 12 mM Glu and 100 µM NMDA, concentrations giving maximal NMDA-receptor-mediated currents in the highly responsive neurons, showed a statistically significantly smaller peak amplitude for Glu-induced currents compared with maximal NMDA-induced currents (P < 0.001, Mann-Whitney U test; Fig. 2, B and C). NMDA and the major part of Glu-induced currents appear to be NMDA-receptor-mediated because they were blocked by the noncompetitive NMDA receptor antagonist MK-801 (50 µM; by 99 ± 0.3% and 78 ± 4%; n = 4 and 6, respectively; Fig. 3). Responses remaining to 12 mM Glu after NMDA receptor block were further reduced in a reversible manner by increasing the concentration of the competitive non-NMDA receptor antagonist, NBQX, from 10 to 20 µM (by a total of 82 ± 5%; n = 5).
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Attenuation of NMDA-induced currents
Glutamate receptor desensitization has been suggested as a mechanism underlying the absence of Glu excitatory action (Yoshimura and Jessell 1990). To determine whether glutamate receptor desensitization accounts for the relatively small Glu-evoked currents we noted, Glu and NMDA were superfused simultaneously to examine possible desensitization effects of Glu on NMDA-induced currents. Coapplication of Glu (12 mM) and NMDA (100 µM) attenuated NMDA-induced currents (by 52 ± 7%; n = 4; Fig. 4A). Figure 4B illustrates a similar experiment in which Glu was applied immediately before NMDA. The average duration of Glu/NMDA current lasted 51 ± 4 s (n = 5) from peak to peak. In this case, NMDA-induced currents were statistically significantly attenuated by Glu (P < 0.05 1-way repeated measure ANOVA; n = 5). In two of these five neurons, NMDA-induced currents remained fully depressed for 5 and 15 min after Glu application. In the remaining three neurons, NMDA-induced currents partially recovered 5 min after Glu application and were completely reversed after 15 min. The time course of these long- and short-lasting depressions (LLD and SLD) relate in time to what has previously been referred to as long- and short-term depression (LTD and STD) (Pockett 1995
; Weisskopf et al. 1993
). The pooled average depressions compared with the control NMDA-induced current were 53 ± 14% (P < 0.05 Newman-Keuls post hoc test), 48 ± 15% (P < 0.05 Newman-Keuls post hoc test), and 23 ± 22% at 0, 5, and 15 min, respectively. These findings are in contrast to individual Glu and NMDA applications in alternating order at 5-min intervals for up to a total of six agonist applications, where peak current amplitudes for Glu remained unchanged (P > 0.05 1-way repeated measure ANOVA; n = 8) and where NMDA-induced currents decreased only slightly, but still statistically significantly, after a third NMDA application (P < 0.01 1-way repeated measure ANOVA; n = 5) compared with the initial NMDA-receptor-mediated currents (i.e., virtually no rundown of NMDA-induced currents were noted during a 25-min period during control conditions). The average Glu-induced currents were 102 ± 13% (2nd application; n = 8) and 100 ± 16% (3rd application; n = 8) of the initial current. The average NMDA-induced currents were 97 ± 2% (2nd application; n = 5) and 87 ± 3% (3rd application; P < 0.01 Newman-Keuls post hoc test; n = 5) of the initial current.
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KA-induced depression of NMDA currents
Glu acts as a mixed agonist for all classes of EAA receptors (Watkins and Evans 1981). To elucidate the glutamate receptor class involved in the Glu inhibitory effects on NMDA receptors, we tested the actions of KA on NMDA-induced currents. KA (100 µM) applied immediately before NMDA evoked small inward currents by itself (29 ± 6 pA; n = 7) and significantly suppressed NMDA-induced currents (P < 0.01 1-way repeated measure ANOVA; n = 7; Fig. 4C). In five of these seven neurons, KA induced a LLD of NMDA-induced currents. In the remaining two neurons, KA induced a SLD of NMDA currents that began 5 min after KA application and reversed completely after 15 min (e.g., Fig. 5B). The pooled average depression compared with the control NMDA-induced current were 24 ± 14% (P < 0.05 Newman-Keuls post hoc test), 45 ± 11% (P < 0.01 Newman-Keuls post hoc test), and 39 ± 15% (P < 0.01 Newman-Keuls post hoc test) at 0, 5, and 15 min, respectively.
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Attenuation of NMDA-receptor-mediated synaptic currents
Bath application of agonist can affect synaptic as well as extrasynaptic receptors. To verify that the present in vitro model has implications for synaptic transmission, we examined Glu and KA depressing effects on NMDA-receptor-mediated EPSCs evoked by dorsal root stimulation. Application of Glu or KA immediately before NMDA application attenuated dorsal root-evoked EPSCs (by 64 ± 17%; Fig. 5A) in three of four neurons when AMPA receptors were blocked by NBQX. As shown in Fig. 5, changes in NMDA-receptor-mediated EPSCs after Glu/NMDA or KA/NMDA application correlate closely in magnitude and time course with changes in bath applied NMDA-induced currents (r = 0.98; P < 0.05; n = 4).
Potentiating effects on Glu-induced currents by low-affinity KA receptor antagonist
The action of a novel KA receptor antagonist, NS-102, on Glu-induced currents in Ca2+-free ACSF was examined for two reasons: first, to determine whether the small Glu-evoked currents observed in some cells are related to Glu's own inhibitory action on Glu-induced NMDA receptor-mediated currents and second, to determine whether these receptors are located pre- or postsynaptically. As shown in Fig. 6, maximal Glu (12 mM)-evoked currents in the presence of NS-102 (10 µM), were significantly augmented (by 157 ± 33%; P < 0.01 Wilcoxon matched pairs test; n = 11) relative to control amplitudes in Ca2+-free ASCF. In 2 of these 11 neurons, NS-102 enhanced Glu (12 mM)-induced currents to a peak amplitude similar (97 ± 1%) to those produced by NMDA (100 µM).
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). Because the effect of NS-102 at mGluR is not known to our knowledge, we investigated the involvement of mGluR by coapplication of NMDA with the mGluR agonist trans-ACPD (200 µM). However, mGluR activation did not significantly alter the NMDA-induced current (91 ± 3% of control; P > 0.05 Wilcoxon matched pairs test; n = 3).
Description of Glu responses compared with dorsal root input
There was a trend, although not statistically significant (P > 0.05, 2 test), that the majority of neurons with small Glu-induced currents were activated by primary afferent activity in A fibers [A only (33/49) and A + C (9/11)]. Those neurons showing inhibitory input (outward current I; 13/15) also tended to have small Glu-induced currents. On the other hand, there appeared to be no correlation between C only activity and magnitude of Glu-evoked responses. These results are summarized in Table 1.
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Effects of Ca2+ on Glu-induced currents
Comparison between Glu-induced peak current amplitudes evoked in normal Ca2+-containing ACSF and Ca2+-free ASCF, respectively, was used to evaluate possible counteracting effects due to the release of inhibitory neurotransmitters on Glu-evoked responses. Both Ca2+-containing ACSF and Ca2+-free ASCF contained 1 µM TTX and 10 µM NBQX. Figure 7 illustrates that mean Glu (12 mM)-induced currents evoked in Ca2+-free ACSF displayed a small (+38%) but statistically significantly increased peak amplitude compared with corresponding control currents in the same neurons in normal ACSF (440 ± 130 pA and 319 ± 104 pA, respectively; P < 0.01 paired t-test; n = 14). However, Glu (12 mM)-induced currents were still significantly smaller compared with NMDA (100 µM)-induced currents in Ca 2+-free ASCF (data not shown), which suggests a postsynaptic mechanism.
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DISCUSSION |
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These observations indicate the presence of a novel mechanism in rat superficial dorsal horn by which KA receptors induce LLD or SLD of both synaptic- and agent-induced NMDA-receptor-mediated excitatory currents. The findings may relate to classical LTD and add a new mechanism, to the list of potential mechanisms of LTD induction (for reviews, see Asztely and Gustafsson 1996; Linden and Connor 1995
) in which Glu, at concentrations sufficient to activate NMDA receptors, can modulate NMDA-induced currents through postsynaptic KA receptors.
, they represent physiologically relevant levels (i.e., micromolar to low millimolar) at the receptor sites considering cellular uptake of Glu in a slice (Garthwaite 1985
). In addition, as indicated by the dose-response curves, the Glu concentrations used were sufficient to fully activate NMDA receptors, with NBQX preventing substantial activation of AMPA receptors. This is supported by the observation that most of the 12 mM Glu-induced responses were blocked by MK-801.
), although discrepancies in the number of Glu-responding neurons in these studies may be related to differences in the recording techniques employed (i.e., tight-seal whole cell recording versus sharp intracellular electrodes) and the Glu concentrations used.
), we find that coapplication of Glu and NMDA, as well as application of Glu directly before NMDA, results in a depression of NMDA-induced currents that is more closely related to the time course of LTD or STD (lasting minutes to hours) (Pockett 1995
; Weisskopf et al. 1993
) than receptor desensitization (lasting seconds) (Mayer et al. 1989
). A recent report proposed the involvement of low-affinity KA receptors in the depression of NMDA-receptor-mediated currents (Chittajallu et al. 1996
). We tested this possibility by applying KA directly before NMDA application. KA mimicked Glu-induced LLD and SLD of NMDA-induced currents.
; Ekerot and Kano 1989
; Linden and Connor 1995
). In the present study, it appears as if simultaneous activation of KA and NMDA receptors by Glu only produces an acute depression, whereas a longer-lasting stimulus in sequence at KA and NMDA receptors by KA or Glu plus NMDA results in a long-lasting depression. However, the timing necessary for induction of such long-lasting depression requires further investigation.
) with a high degree of selectivity for low-affinity KA receptors over other ionotropic EAA receptors (Johansen et al. 1993
). Therefore, we hypothesize that the complete or partial recovery of Glu currents by NS-102 involves native low-affinity KA receptors composed of GluR6 subunits in either homomeric (Bettler et al. 1992
; Egebjerg et al. 1991
) or heteromeric (Herb et al. 1992
) complexes.
. The exact intracellular mechanism involved in KA-receptor-induced LLD remains unresolved. It is known that KA receptor channels are permeable to Na+ and Ca2+ (Egebjerg and Heinemann 1993
; Köhler et al. 1993
). Thus one possibility for LLD induction is Na+ influx, consistent with some types of AMPA-induced synaptic plasticity (Linden et al. 1993
; Shaw et al. 1994
). Alternatively, other observations indicate a dependence of LTD-induction on elevation of the intracellular Ca2+-levels (Barry et al. 1996
; Cummings et al. 1996
). Our observation that Glu-induced currents are depressed in Ca2+-free medium argues against extracellular Ca2+ influx; however, Ca2+ mobilized from intracellular stores is possible but a less likely mechanism because the intracellular calcium is strongly buffered in the present study.
). However, the findings by Medina et al. (1994)
are quite different from our findings because their inactivation of NMDA-induced currents by KA was studied in the absence of an AMPA receptor blocker and thus was likely to be partly mediated by activation of AMPA receptors (Bettler and Mulle 1995
) and because their inactivation was dependent on the extracellular calcium concentration and disappeared during strong intracellular calcium buffering. It is possible that the comparably slow KA-induced inactivation of NMDA-induced currents reported by Medina et al. (1994)
is mediated by two distinct mechanisms, one dependent on elevation of intracellular calcium and a second mechanism, similar to the one in the present study, that is mediated through activation of low-affinity KA receptors.
) and with findings by Clark et al. (1997)
that synaptic and extrasynaptic NMDA receptors behave in a similar manner. It suggests that the present findings have implications for synaptic transmission in this part of the CNS.
. However, unlike their results, we find that nearly all neurons receiving excitation from both A and C fibers also have small Glu-evoked responses. These results suggest that the majority of neurons activated by A
fibers (including A and A + C) may have small Glu-induced currents. One possible explanation for this difference in observation is the difference in recording sites between the two studies; our recordings were in the lateral portion of the SG and those of Schneider and Perl (1985)
were more medial. Association of neurons responding with small Glu-evoked currents to A
but not C fibers also may relate to the recent findings by Yajiri et al. (1997)
, who demonstrate a novel presumably EAA-mediated slow synaptic current that is associated with activity in A
fibers. This slow synaptic current may relate to the present findings with KA.
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ACKNOWLEDGEMENTS |
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We thank Dr. E. R. Perl for constructive comments on the manuscript.
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FOOTNOTES |
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Address reprint requests to J. Näsström.
Received 11 July 1997; accepted in final form 31 March 1998.
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REFERENCES |
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