Physiologisches Institut der Universität Würzburg, D-97070 Würzburg, Germany
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Nebe, Johannes,
Andrea Ebersberger,
Horacio Vanegas, and
Hans-Georg Schaible.
Effects of -agatoxin IVA, a P-type calcium channel antagonist, on
the development of spinal neuronal hyperexcitability caused by knee
inflammation in rats. Both N- and P-type high-threshold calcium channels are located presynaptically in the CNS and are involved in the release of transmitters. To investigate the importance of P-type calcium channels in the generation of inflammation-evoked hyperexcitability of spinal cord neurons, electrophysiological recordings were made from wide-dynamic-range neurons with input from
the knee joint in the anesthetized rat. The responses of each neuron to
innocuous and noxious pressure onto the knee and the ankle were
continuously assessed before and during the development of an
inflammation in the knee joint induced by the injections of K/C into
the joint cavity. The specific antagonist at P-type calcium channels
-agatoxin was administered into a 30-µl trough on the spinal cord
surface above the recorded neuron. In most neurons the application of
-agatoxin before induction of inflammation slightly enhanced the
responses to pressure onto the knee and ankle or left them unchanged.
Two different protocols were then followed. In the control group (13 rats) only Tyrode was administered to the spinal cord during and after
induction of inflammation. In these neurons the responses to mechanical
stimuli applied to both the inflamed knee and to the noninflamed ankle
showed a significant increase over 4 h. In the experimental group
(12 rats)
-agatoxin was applied during knee injection and in five
15-min periods up to 180 min after kaolin. This prevented the increase
of the neuronal responses to innocuous pressure onto the knee and to
innocuous and noxious pressure onto the ankle; only the responses to
noxious pressure onto the knee were significantly enhanced during
development of inflammation. Thus the development of
inflammation-evoked hyperexcitability was attenuated by
-agatoxin,
and this suggests that P-type calcium channels in the spinal cord are
involved in the generation of inflammation-evoked hyperexcitability of
spinal cord neurons. Finally, when
-agatoxin was administered to the
spinal cord 4 h after the kaolin injection, i.e., when
inflammation-evoked hyperexcitability was fully established, the
responses to innocuous and noxious pressure onto the knee were reduced
by 20-30% on average. The shift in the effect of
-agatoxin, from
slight facilitation or no change of the responses before inflammation
to inhibition in the state of hyperexcitability, indicates that P-type
calcium channels are important for excitatory synaptic transmission
involved in the maintenance of inflammation-evoked hyperexcitability.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In neurobiological research on nociception and
pain, the functional role of diverse types of ion channels in
nociceptive neurons has recently elicited considerable interest.
Because neuronal calcium channels play a critical role in the release
of neuromediators and in somatodendritic excitability (Bertolino
and Llinas 1992; Miljanich and Ramachandran
1995
; Olivera et al. 1994
; Tsien
1993
), their participation in the mechanisms of acute and
persistent nociception has become a focus of recent investigations.
Electrophysiological, pharmacological, and molecular genetic techniques
have identified high-threshold voltage-dependent calcium channels
(VDCCs) of the L, N, P, Q or P/Q, and R type in central neurons
(Miljanich and Ramachandran 1995
; Olivera et al.
1994
; Tsien 1993
).
P-type VDCCs are located in presynaptic neuronal terminals, and they
are involved in the release of the transmitters glutamate, aspartate,
dopamine, serotonin, norepinephrine, GABA, and probably glycine and
presumably others (Kimura et al. 1995; Miljanich
and Ramachandran 1995
; Takahashi and Momiyama
1993
; Turner et al. 1992
, 1993
). The potent and
selective antagonist of P-type calcium channels
-agatoxin IVA
(AgaIVA) can be used to identify P-type-calcium-dependent synaptic and
other cellular processes. AgaIVA has been shown to block excitatory
(Castillo et al. 1994
; Luebke et al.
1993
; Yamamoto et al. 1994
) as well as
inhibitory synaptic transmission (Takahashi and Momiyama
1993
). P-type channels may sustain pre- as well as postsynaptic
calcium currents (Igelmund et al. 1996
).
Behavioral and electrophysiological experiments showed an involvement
of P-type calcium channels in spinal nociceptive processing under
particular conditions. In awake rats, intrathecal administration of
AgaIVA decreased the late phase of nociceptive behavior in the formalin
test (Malmberg and Yaksh 1994). The development of secondary hyperalgesia and allodynia after the intradermal injection of
capsaicin (Sluka 1997
) or the induction of an
inflammation in the knee joint (Sluka 1998
) could be
prevented by the application of AgaIVA through a microdialysis fiber
implanted in the spinal dorsal horn. In recordings from spinal cord
neurons, AgaIVA reduced the discharges of nociceptive neurons in the
late phase of the formalin response (Diaz and Dickenson
1997
). In spinal cord neurons with input from the knee joint,
AgaIVA administration to the spinal cord caused on average a slight
facilitation of dorsal horn neuronal responses to innocuous and noxious
pressure applied to a normal knee; however, in rats in which the knee
had been inflamed for a few hours with kaolin/carrageenan, AgaIVA
reduced the responses to innocuous and noxious pressure by ~27%
(Nebe et al. 1997
). These findings suggest that P-type
VDCC-dependent processes are involved in the spinal cord processing of
input from inflamed tissue.
We addressed the question whether P-type VDCCs are involved in the
generation of inflammation-evoked hyperexcitability of spinal cord
neurons. Because our previous study (Nebe et al. 1997) was done in one population of rats with normal knees and in another population with one knee inflamed, information could only be obtained regarding the involvement of P-type channels in the maintenance but not
in the generation of inflammation-evoked hyperexcitability. The latter
process requires the intraspinal release of several transmitters and
neuromodulators such as excitatory amino acids and the neuropeptides
substance P, neurokinin A, and calcitonin gene-related peptide and
probably others and the activation of the corresponding receptors (for
references see Neugebauer et al. 1993
-1995
, 1996a
,b
).
These systems are likewise involved in other models of persistent
nociception (cf. Coderre et al. 1993
; Dubner and
Ruda 1992
; Willis 1994
).
If P-type VDCCs are involved in the release of transmitters and
modulators that are important for the generation of inflammation-evoked hyperexcitability, then the application of AgaIVA should have an
influence on the progressive increase of neuronal responses that is
seen during the development of inflammation (Schaible and Grubb
1993). We therefore administered AgaIVA to the spinal cord
before and during the induction of knee inflammation and studied
whether this treatment would interfere with the central sensitization
process that is usually seen under these conditions.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Preparation
Experiments were performed on 25 male Wistar rats (280-440 g) anesthetized with sodium thiopentone (Trapanal, BYK, initial dose 85-115 mg/kg ip). The trachea was cannulated, and catheters were inserted into the common carotid artery and the external jugular vein. The animals breathed spontaneously, and a gentle jet of oxygen was blown toward the opening of the tracheal cannula. Body temperature was kept at 37°C by means of a feedback-controlled system. Additional injections of thiopentone (20-50 mg/kg ip) were given as necessary to achieve a sufficiently deep level of anesthesia as assessed by the absence of corneal or leg withdrawal reflexes. Mean arterial blood pressure was stable at 90-120 mmHg. Spinal cord segments L1-L4 were exposed by laminectomy. The dura mater was opened, and a thin-walled, ellyptic rubber ring (~3 × 5 mm) was tightly sealed with silicone gel onto the surface of the cord. This ring thus formed a trough with ~30 µl capacity over the spinal segments in which the recordings were to be performed. This trough was immediately filled with Tyrode. A solution of 3% agar in Tyrode was poured around the trough to seal and stabilize the surgical area.
Recording and sampling of neurons
By using glass-insulated carbon filaments for recording, individual neurons were identified by spike shape and height. The action potentials were continuously monitored on a digital oscilloscope and recorded on videotape. The signal was also fed into a window discriminator, the output of which was processed by an A/D interface and a personal computer so that peristimulus time histograms could be constructed. Dorsal horn neurons were chosen for study if they responded to pressure applied to the ipsilateral left knee but did not respond to brushing or squeezing of the skin over the knee. The size of and the threshold within receptive fields were determined with stimulation of the skin (brushing, squeezing of skin folds with forceps) and of the deep tissue (compression of joints and muscles). Only neurons were studied that responded to innocuous mechanical stimuli and showed stronger responses to noxious mechanical stimuli (wide-dynamic-range neurons). Mechanical test stimuli of two standard intensities were then applied to the knee and to the ankle. A calibrated mechanical device was used for compression of the knee joint in the mediolateral axis; for innocuous intensity, a 1.9 N/40 mm2 holding pressure was applied, and for noxious intensity (felt painful when applied to the experimenter's fifth finger) the knee was compressed with either 5.9 or 7.8 N/40 mm2. Two clips were used for stimulation at the ipsilateral ankle (1.1 N/20 mm2 for innocuous, 5.8 N/20 mm2 for noxious stimulation). Each pressure stimulus lasted for 15 s. Each neuron was continuously recorded before and through the development of knee inflammation.
Experimental protocol
Innocuous and noxious test stimuli were applied sequentially to the knee and then to the ankle; this sequence was repeated every 3-5 min, even when the manipulations described subsequently were being carried out. In 13 control rats (the Tyrode group, see Fig. 1A), after the neuronal baseline responses were established during 1 h, the Tyrode solution was removed from the trough, and 20 µl of 0.1 µM AgaIVA (either a gift from Pfizer or purchased from Peninsula) in 165 mM NaCl, pH 7.0, was delivered to the trough with an Eppendorf pipetter. AgaIVA remained in the trough for 30 min (Fig. 1A), and then the trough was rinsed three times and refilled with Tyrode. Thirty minutes later, an experimental inflammation was induced in the left knee joint. With this purpose a 27-gauge needle was introduced through the patellar ligament, and 70 µl of a 4% kaolin suspension was slowly injected into the articular cavity. Then the joint was slowly flexed and extended for 15 min. Thereafter, 70 µl of a 2% carrageenan solution was injected, and the joint was moved for another 5 min. Forty-five minutes after the kaolin injection, a period began in which Tyrode was exchanged in the trough every 15 min up to 180 min after kaolin. One hour after the last Tyrode change, a final application of AgaIVA of 30-min duration was made (Fig. 1A). In another 13 rats (the AgaIVA-group, see Fig. 1B), the influence of AgaIVA on the increases of responses to mechanical stimuli during the development of inflammation was assessed. The protocol was similar as in the Tyrode group except that 1) the first AgaIVA application lasted for 1 h and the kaolin/carrageenan injection was performed in the middle of this period (Fig. 1B) and 2) between 45 and 180 min after kaolin AgaIVA and Tyrode were alternated in the trough every 15 min (Fig. 1B).
|
Quantification of results
The responses to pressure stimuli were calculated by subtracting the ongoing activity in the preceding 15 s (if any) from the total activity during an innocuous or a noxious test stimulus. To establish the predrug baseline of a neuron, ~10 test responses to each type of stimulus were averaged and set to 0. The responses of the neuron to mechanical stimuli after the induction of inflammation were grouped in the following time intervals: baseline before the first application of AgaIVA, during the 30 min of the first application of AgaIVA, 30-90 min, 90-150 min, 150-210 min, and 210-240 min after kaolin. The intraarticular injection of kaolin was taken as minute 0, and an average value was calculated of the responses to innocuous or noxious stimulation in each of these time intervals. The baseline average was set to 0, and all other average values were compared with it (see Fig. 2). Wilcoxon matched-pairs signed rank test was used to analyze inflammation-evoked changes of responses within the treatment groups. The Mann-Whitney U test was used to compare the mean values of corresponding time periods between the groups of neurons. To evaluate the effect of the two 30-min applications of AgaIVA before and after development of inflammation (see Figs. 1 and 3), the average of the responses during application was expressed as percentage of the average responses during the 30 min preceding the application. Changes in responses were analyzed by means of the Wilcoxon matched-pairs signed rank test. Significance was acknowledged if P < 0.05.
|
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In 25 rats recordings were performed from 26 neurons with input from the ipsilateral knee joint (in 1 experiment 2 neurons were monitored simultaneously). The neurons were located in segments L1-L3 at depths of 353-1136 µm (809 ± 194 µm, mean ± SD). The large majority of neurons was thus in the deep dorsal horn. All recorded cells were wide-dynamic-range neurons. Only 4 of 26 neurons showed ongoing discharges before inflammation. The neurons were activated by pressure onto the knee and other deep tissues of the leg (e.g., the ankle). Most of the neurons had also cutaneous receptive fields on the leg but not in the skin overlying the knee.
Effect of AgaIVA on the development of inflammation-induced hyperexcitability
MECHANICAL STIMULATION OF THE KNEE JOINT. Figure 1 shows results from two dorsal horn neurons from two experiments. The graphs display the responses to innocuous and noxious pressure applied to the knee joint before inflammation and during the development of inflammation that was induced by the intraarticular injections of kaolin and carrageenan (K/C). Before induction of inflammation, AgaIVA was administered topically to the spinal cord for a period of 30 min. In this period neither of these neurons showed a consistent change of the responses to innocuous and noxious pressure during the administration of AgaIVA (see time blocks before K/C in Fig. 1).
After testing the effect of AgaIVA before inflammation, K/C were injected into the knee for induction of inflammation, and changes of the responses to innocuous and noxious pressure were monitored. In the control neuron in Fig. 1A, fresh Tyrode solution was administered to the spinal cord during the time blocks indicated. In the neuron in Fig. 1B, AgaIVA was left on the cord for 30 min after the injection of kaolin (initial phase of the induction of inflammation) and was also administered for several periods of 15 min between 45 and 180 min after injection of kaolin (Fig. 1B, shaded rectangles). In both neurons the responses to innocuous and noxious pressure applied to the knee showed an increase during development of inflammation, although the relative changes in the AgaIVA-treated neuron were less pronounced. In both neurons, AgaIVA was then administered for 30 min to the spinal cord surface beginning 240 min after kaolin. At this stage, the responses to pressure showed a decrease during the administration of the antagonist in both neurons. In the total sample of 13 neurons from control experiments, in which only Tyrode was administered to the spinal cord during development of inflammation (cf. Fig. 1A), 12 neurons showed an increase of the responses to innocuous pressure onto the knee, and 10 neurons also exhibited an increase to noxious pressure. In the sample of 13 neurons from experiments in which AgaIVA was administered to the spinal cord during the development of inflammation, 8 neurons showed an increase of the responses to innocuous and noxious pressure, whereas 5 neurons exhibited rather decreases of the responses. In both groups of experiments, the diameter of the injected knee joint showed a similar increase (from 55 to 59 mm in the Tyrode control group and from 56 to 61 mm in the rats in which AgaIVA was administered to the spinal cord during development of inflammation). Figure 2, left panel, summarizes the average changes of the responses to innocuous (top) and noxious pressure (bottom) onto the knee during development of inflammation in all neurons from Tyrode control experiments (MECHANICAL STIMULATION OF THE ANKLE. Figure 3A shows the responses of a neuron to innocuous and noxious pressure onto the ankle before and during development of inflammation in the injected knee from a control experiment in which only Tyrode was administered to the spinal cord. Figure 3B displays a neuron from an experiment in which AgaIVA was administered to the spinal cord during the development of inflammation. Although the neuron in Fig. 3A showed an increase of the responses to innocuous and noxious pressure onto the ankle during development of inflammation in the knee, the neuron in the AgaIVA-treated rat did not (Fig. 3B).
In control experiments in which only Tyrode was administered to the spinal cord during development of inflammation, 9 of 10 neurons that had ankle input showed an increase of the responses to innocuous and noxious pressure. In the sample of nine neurons from experiments in which AgaIVA was administered to the spinal cord during the development of inflammation, only two neurons showed an increase of the responses to innocuous pressure, and three neurons exhibited an increase of the responses to noxious pressure. Figure 2, right panel, shows the average changes of responses to mechanical stimulation of the ankle in all 10 neurons from control rats with ankle input (Differences in the effects of 30-min applications of AgaIVA before inflammation versus 240-270 min after kaolin
A 30-min application of AgaIVA before inflammation (cf. Fig. 1, left side of the K/C line) had variable effects on the responses of the neurons. Indeed before inflammation the responses to mechanical stimulation of the knee and ankle were either unchanged, slightly enhanced, or slightly inhibited by AgaIVA. Responses to stimulation of the knee are displayed in Fig. 4 where the values on the left in each of the four sets show the changes of the responses during the administration of AgaIVA before inflammation. By contrast, in the presence of inflammation and therefore hyperexcitability, the majority of the neurons shifted to a decrease of the responses to innocuous and noxious pressure applied to the knee joint under the effect of AgaIVA (see Fig. 1 and Fig. 4, values on the right of each set). This change of the effect of AgaIVA on one and the same neuron was statistically significant (Wilcoxon matched-pairs signed rank test) whether the spinal cord was treated only with Tyrode solution (control) or with AgaIVA (AgaIVA blocks) during development of inflammation. Regarding the responses to mechanical stimulation of the ankle, the responses to innocuous and noxious pressure in the Tyrode group were less facilitated by AgaIVA during inflammation than before inflammation (significant in the Wilcoxon matched-pairs signed rank test), but only very few neurons showed a shift from facilitation to depression of the responses. In neurons from experiments in which AgaIVA was repeatedly administered to the spinal cord during development of inflammation and therefore developed no hyperexcitability to ankle stimulation, there was no significant difference between the effect of 30-min application of AgaIVA before versus during inflammation.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The current experiments showed that the administration of AgaIVA to the spinal cord during the development of inflammation of the knee joint influenced the generation of hyperexcitability of dorsal horn neurons. When only Tyrode was administered to the spinal cord during the development of inflammation, the responses to mechanical stimuli applied to the injected knee and to the noninjected ankle showed a significant increase. By contrast, the changes of the responses were smaller in rats in which AgaIVA was applied to the spinal cord during development of inflammation. Indeed in these rats only the responses to noxious pressure onto the knee showed a significant increase, whereas the responses to innocuous pressure onto the knee and the responses to pressure onto the ankle did not change significantly. The data suggest therefore that P-type calcium channels in the spinal cord are involved in the generation and development of inflammation-evoked hyperexcitability of spinal cord neurons. Furthermore, these experiments showed that the effect of a 30-min application of AgaIVA on the responses of one and the same neuron to knee stimulation switches from inconsistent to inhibitory when an inflammation develops in the knee. Thus P-type VDCCs seem to be involved in the maintenance of established hyperexcitability.
As in the previous study, AgaIVA was administered at a dose that was
found in in vitro studies to be specific for the blockade of P-type
VDCCs (for references see Nebe et al. 1997). AgaIVA was
not continuously administered to the spinal cord but for periods of
15-30 min. This approach resembles the protocol that we had used
before to study the effect of antagonists at glutamate and neuropeptide
receptors on the development of hyperexcitability (Neugebauer et
al. 1993
, 1995
, 1996a
,b
). The protocol of repeated applications
has the advantage that the spinal cord is exposed to relatively
reproducible dosages throughout the experiments. The intervals between
the AgaIVA blocks allowed to test whether AgaIVA had immediate effects
on the responses. Because this was not the case, all values in the
defined time periods were averaged to determine the mean responses
during these periods.
The features of the development of hyperexcitability, i.e., an increase
of the responses to mechanical stimulation of the injected knee as well
as an increase of the responses to mechanical stimulation of the
noninflamed ankle, are in line with the results of our previous studies
(Neugebauer et al. 1993-1995
, 1996a
,b
; Schaible
and Grubb 1993
). However, the effects of inflammation on the
spinal cord neurons seem to be quantitatively smaller in experiments in
which a trough is placed on the spinal cord surface to administer
compounds topically to the spinal cord. From a number of different
studies, the concept emerged that inflammation-evoked hyperalgesia
results from a sensitization of both primary afferent and spinal cord
nociceptive neurons. The increase in the responses to stimulation of
the inflamed knee most likely constitutes the neuronal basis of primary
hyperalgesia, whereas the increase in the responses of the neurons to
stimulation of the noninflamed ankle may correspond to the development
of secondary hyperalgesia that is observed outside of the inflamed or
injured area (Coderre et al. 1993
; Dubner and
Ruda 1992
; McMahon et al. 1993
; Schaible and Grubb 1993
; Willis 1994
).
Changes of the responses to mechanical stimulation of the inflamed knee
were not totally prevented by AgaIVA. When hyperexcitability was
established the administration of AgaIVA consistently reduced the
responses to stimulation of the knee on average by 20-30%. The latter
effect is within the range of P-type VDCC contribution in various
physiological processes (Brown et al. 1994; Mintz
et al. 1992
; Rusin and Moises 1995
;
Turner et al. 1993
). Thus P-type VDCCs seem to be
involved in the generation and maintenance of primary hyperalgesia
after joint inflammation, but on the other hand AgaIVA had only limited
effectiveness. This is best explained by the fact that N-type VDCCs
significantly contribute to the nociceptive synaptic processing and the
generation of hyperexcitability (Diaz and Dickenson
1997
; Nebe et al. 1998
; Neugebauer et al. 1996c
; Sluka 1998
) and that the effect of
different types of VDCCs is additive (Nebe et al. 1997
).
By contrast, the responses to mechanical stimulation of the ankle did
not show increases during development of inflammation in the knee when
AgaIVA was administered to the spinal cord. Thus P-type VDCCs seem to
be critically involved in the generation of secondary hyperalgesia
after inflammation. These results are in general accordance with
behavioral studies that showed that secondary heat hyperalgesia and
allodynia after the induction of inflammation in the knee joint could
be prevented by the application of AgaIVA through a microdialysis fiber
implanted in the spinal dorsal horn (Sluka 1998). On the
other hand, when hyperexcitability to knee stimulation was established,
the responses to pressure onto the ankle were less facilitated by
AgaIVA, but on average no inhibition of the responses was observed
(Nebe et al. 1997
). This may correspond to the finding
that in awake rats secondary heat hyperalgesia could not be reversed
when AgaIVA was given after induction of inflammation (Sluka
1998
).
P-type VDCCs are mainly located at presynaptic sites where they
regulate the release of compounds. The pattern of effects of AgaIVA in
this study suggests that P-type VDCCs are involved in the spinal
nociceptive processing in a complex fashion. First, the responses to
mechanical stimulation of the knee before inflammation were not
consistently reduced by AgaIVA. Either P-type VDCCs are not functional
in this situation or they are involved in the release of both
excitatory and inhibitory transmitters (Mintz et al.
1992; Takahashi and Momiyama 1993
) such that the
net responses to mechanical stimulation are either slightly enhanced,
reduced, or unchanged when P-type VDCCs are blocked by AgaIVA. Second,
during development of inflammation AgaIVA most likely blocked the
additional release of excitatory compounds. Candidates are excitatory
amino acids such as glutamate and neuropeptides such as substance P and
CGRP because the release of these compounds is enhanced in this model of inflammation (Schaible et al. 1990
, 1994
;
Sluka and Westlund 1992
). During this process AgaIVA
obviously acted in the neuronal pathways that are involved in the
generation of primary and secondary hyperalgesia. Third, when the
hyperexcitability is developed, P-type VDCCs seem to be mainly involved
in the maintenance of the enhanced responses evoked by stimulation of
the inflamed knee, and they seem to be less important in the pathways
activated by stimulation of the noninflamed tissues such as the ankle
(Nebe et al. 1997
; Sluka 1998
). Thus the
involvement of P-type VDCCs in synaptic responses is more dependent on
particular conditions than the involvement of N-type VDCCs. It is not
precisely known at this stage how the change in effectiveness of AgaIVA
in different phases of inflammation can be explained. At present we do
not know which neuronal mechanisms bring P-type VDCCs into play.
Furthermore, we do not know in which types of neurons (primary afferent
neurons, interneurons) P-type VDCCs are expressed and which
transmitters are particularly released by activating presynaptic P-type VDCCs.
As mentioned previously, N-type VDCCs seem to be involved in the
synaptic nociceptive processing in a more uniform way than P-type
VDCCs. Indeed, N-type VDCCs are activated during synaptic processing of
input from the normal and from the inflamed tissue (Diaz and
Dickenson 1997; Malmberg and Yaksh 1994
;
Neugebauer et al. 1996c
). Furthermore,
-conotoxin
GVIA, a selective antagonist at N-type VDCCs, reduces nociceptive
responses to ~50% (Neugebauer et al. 1996c
), thus
suggesting that N-type VDCCs play a quantitatively greater role than
P-type VDCCs in the synaptic processing in the spinal cord.
In summary, this study showed that P-type VDCCs are involved in the generation of inflammation-evoked hyperexcitability of spinal cord neurons. Furthermore, the results emphasize a role of P-type VDCCs in the maintenance of hyperexcitability once it is established. The blockade of P-type VDCCs may therefore be considered a target for the prevention or reduction of inflammation-evoked pain. However, because of the limited effectiveness of AgaIVA, it is unlikely that the blockade of P-type VDCCs alone will be sufficient to reduce inflammation-evoked hyperalgesia and pain.
![]() |
ACKNOWLEDGMENTS |
---|
T. Hoffmann provided excellent technical assistance.
This project was supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB-353). J. Nebe was a DFG postdoctoral fellow. H. Vanegas's stay in Würzburg was supported by the Alexander-von-Humboldt-Stiftung.
![]() |
FOOTNOTES |
---|
Present address and address for reprint requests: H.-G. Schaible, Institut für Physiologie, Friedrich-Schiller-Universität Jena, Teichgraben 8, D-07740 Jena, Germany.
Present address: J. Nebe, Rheinische Landes- und Hochschulklinik Essen, Virchowstr. 174, D-45147 Essen, Germany; A. Ebersberger, Institut für Physiologie, Friedrich-Schiller-Universität Jena, Teichgraben 8, D-07740 Jena, Germany; H. Vanegas, Instituto Venezolano de Investigaciones Cientificas, Apt. 21827, 1020-A Caracas, Venezuela.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 13 August 1998; accepted in final form 4 February 1999.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|