Clonidine reduces the excitability of spinal dorsal horn neurones
1 Clinic for Anaesthesiology, Intensive Care Medicine, and Pain Therapy, Giessen, Germany
2 Department of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany
3 Department of Anaesthesiology and Intensive Care Medicine, Medical University Graz, Austria
* Corresponding author: Clinic for Anaesthesiology Intensive Care Medicine, and Pain Therapy, Rudolf-Buchheim-Straße 7, 35392 Giessen, Germany. E-mail: matthias.wolff{at}physiologie.med.uni-giessen.de
Accepted for publication November 29, 2006.
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Abstract |
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BACKGROUND: Clonidine has often been applied in combination with local anaesthetics for spinal or epidural anaesthesia. This study was designed to investigate the local anaesthetic-like action of clonidine in superficial dorsal horn neurones. The superficial laminae of the dorsal horn contain three groups of neurones: tonic-, adapting-, and single-spike-firing neurones which are important neuronal structures for pain transmission, receiving most of their primary sensory input from A
and C fibres. METHODS: Whole cell patch clamp recordings from spinal cord slices of Wistar rats were used to study the action of clonidine on the generation of single and series of action potentials. Voltage clamp recordings in isolated somata were performed to study the effect of clonidine on voltage-gated Na+ and different types of K+ currents.
RESULTS: Firing frequencies of trains of action potentials in tonic-firing neurones are reduced at low concentrations (10 µM) of clonidine, but not in adapting- or single-spike-firing neurones. High concentrations of clonidine (700 µM) are necessary to modify the shape of single action potentials. Low concentrations of clonidine shift the steady-state inactivation curve of Na+ currents to more negative potentials. At clinical concentrations (6–100 µM) clonidine partially inhibits voltage-gated Na+ and K+ channels.
CONCLUSIONS: Clonidine suppresses the generation of action potentials in tonic-firing spinal dorsal horn neurones. This may be explained, in part, by an interaction with voltage-gated Na+ and K+ currents. Clonidine could therefore contribute to analgesia during local anaesthesia.
Keywords: ion channels, voltage gated; pharmacology, clonidine; spinal cord, sensory block
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Introduction |
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Clonidine, an
2-receptor agonist, is widely used during antihypertensive therapy1 and as a co-analgesic during chronic pain therapy.2 In addition, clonidine has been applied locally during spinal or epidural anaesthesia3 and peripheral nerve block.4 Clonidine is also applied preferentially in combination with local anaesthetics3 where clonidine amplifies and prolongs the local anaesthetic effect. Clonidine has also been administered intrathecally, as a sole agent to achieve an analgesic effect in an experimental setting5 and during the first stage of labour.6 The concentration of clonidine in the cerebrospinal fluid after an intrathecal administration ranges from 6 to 100 µM.
During spinal and epidural anaesthesia, the applied drugs diffuse directly into the spinal cord,7 particularly to superficial neurones in laminae I and II of the dorsal horn. Most fine-calibre C- and A-fibres terminate within laminae I and II8, 9 and are therefore considered to be a key element in the nociceptive processing system.
Several classes of superficial dorsal horn neurones are distinguished on the basis of their intrinsic firing properties.10 Tonically-firing neurones (TFNs) were described as exhibiting little spike frequency adaptation during sustained depolarization, and were shown to be either wide-dynamic-range or nociceptive-specific neurones.10 Adapting-firing neurones (AFNs) generate a short burst of spikes at the beginning of depolarization. Most are physiologically classified as nociceptive-specific neurones.10 Single-spike neurones (SSNs) generate only one or seldom two spikes at the beginning of a depolarizing pulse. These neurones could act as coincidence detectors.11
The aim of this study was to investigate the action of clonidine on the generation of action potentials in different types of sensory spinal dorsal horn neurones involved in the nociceptive processing system. Since voltage-gated Na+ and K+ currents are responsible for the generation of action potentials, a possible interaction of clonidine with these ionic currents is described.
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Preparation
Experiments were performed using the patch clamp technique12 13 on 200 µm slices, cut from lumbar enlargements (L3–6) of the spinal cord of 4- to 12-day-old rats of both sexes. Animals were rapidly decapitated and the spinal cords were carefully excised in ice-cold preparation solution bubbled with O2–CO2 (95–5%). After removal of the pial membrane with fine forceps, the spinal cord was embedded in a preparation solution containing 2% agar cooled to 39°C. To accelerate solidification of the agar, the beaker with the preparation was placed in ice-cold water. The agar block containing the lumbar enlargement of the spinal cord was removed and glued to a glass stage fixed in the chamber of the tissue slicer. The spinal cord was sliced in ice-cold preparation solution under continuous bubbling. The slices were thereafter incubated for 45 min at 32°C.
The procedures for animal decapitation have been reported to the local veterinary authority and are in full accordance with German guidelines.
Solutions
External solutions: Preparation solution contained (in mM): NaCl 115, KCl 5.6, CaCl2 2, MgCl2 1, glucose 11, NaH2PO4 1, and NaHCO3 25 (pH 7.4 when bubbled with 95% O2–5% CO2). In the experimental chamber, the slices were superfused by low-Ca2+-solution in order to reduce spontaneous synaptic activity and to prevent activation of Ca2+ currents and Ca2+-dependent K+ currents. Low-Ca2+-solution was obtained from the preparation solution by setting the concentration of Ca2+ to 0.1 mM and increasing the concentration of Mg2+ to 5 mM (in the following referred to as external solution). Tetraethylammonium (TEA)-containing solution used for Na+ current recordings contained (in mM): NaCl 95, KCl 5.6, CaCl2 0.1, MgCl2 5, glucose 11, NaH2PO4 1, NaHCO3 25, and TEA-Cl 20 (pH 7.4 when bubbled with 95% O2–5% CO2). The study of K+ currents was carried out in Na+-free choline-Cl-solution containing (in mM): choline-Cl 141, KCl 0.6, CaCl2 0.1, MgCl2 5, glucose 11, and HEPES 10, pH 7.4 (adjusted with 1 M KOH). KCl was added to give a final K+ concentration of 5.6 mM.
Clonidine was directly added to control solutions. The experimental chamber, with a volume of 0.4 ml, was continuously perfused with external solution at a rate of 2–3 ml min–1; the pH of drug solutions was tested and corrected to eliminate potential pH-induced effects.
Pipette solutions: High K+-1-solution used for action potential recordings from intact neurones contained (in mM): NaCl 5, KCl 144.4, MgCl2 1, EGTA 3, and HEPES 10, pH 7.3 (adjusted with 1 M KOH). KCl was then added to a final K+ concentration of 155 mM. High K+-2-solution used for K+ current recordings in isolated somata contained (in mM): NaCl 5, KCl 144.4, MgCl2 1, EGTA 3, and HEPES 10, pH 7.3 (adjusted with 1 M NaOH). NaCl was then added to a final Na+ concentration of 15 mM. CsCl-solution used for Na+ current recordings contained (in mM): NaCl 5.8, CsCl 134, MgCl2 1, EGTA 3, and HEPES 10, pH 7.3 (adjusted with 1 M NaOH). NaCl was then added to a final Na+ concentration of 15 mM.
Recording conditions
Pipettes pulled from borosilicate glass tubes (GC 150, Clark Electromedical Instruments, Pangbourne, UK) were fire-polished to give a final resistance of 3–7 M
. The patch clamp amplifier was an Axopatch 200B (Axon Instruments, Foster City, CA, USA). In experiments with Na+ currents the effective corner frequency of the low pass filter was 5 kHz, K+ currents were filtered at 1 kHz. The frequency of digitization was twice than that of the filter frequency. In current clamp mode, action potentials were filtered at 5 kHz and sampled at 10 kHz. Data were stored and analysed using pClamp software (version 9.1, Axon Instruments, Foster City, CA, USA). Transient and leakage currents were recorded and digitally subtracted offline in all experiments using averaged records with hyperpolarizing impulses (100 ms voltage steps from – 80 to – 120 mV) that activated no currents. Offset potentials were nullified directly before formation of the seal. The small amplitude of currents recorded in somata (<500 pA) made series resistance compensation unnecessary as in isolated somata the voltage errors because of the resistance in series were smaller than 4 mV. The amplitude of the capacitive transient was monitored and recorded. The input and the series resistances of the somata were calculated from correction file recordings as described above. Neurones were rejected if these parameters varied more than 20% during recording. All experiments were carried out at room temperature (21–23°C).
Na+ currents were studied in external TEA-solution using pipettes filled with CsCl-solution. Currents were activated by a voltage step to – 20 mV after a 50-ms prepulse to – 120 mV, holding potential was – 80 mV. For investigation of use-dependent block (30 pulses at 2 and 10 Hz), no hyperpolarizing prepulse was applied. Steady-state inactivation was studied using 50 ms depolarising pulse to – 20 mV after a 50 ms prepulse to different potentials ranging between – 120 and – 20 mV. K+ currents were recorded in external choline-Cl-solution using pipettes filled with high K+-2-solution. K+ currents were separated by a procedure described previously.14 Total K+ currents activated by depolarizing steps to + 40 mV after a 150-ms prepulse to – 120 mV consisted of both rapidly inactivating A-type (KA) and delayed rectifier (KDR) components. A similar depolarization applied after a 150-ms prepulse to – 60 mV (which almost completely inactivates KA currents) elicited only a non-inactivating component of K+ current, considered to be a KDR current. The amplitudes of the KDR currents were measured at the end of a 250-ms depolarizing pulse. Data from voltage clamp experiments were pooled from all three types of neurones.
Action potentials were recorded using pipettes filled with high K+-1-solution, bath solution was external solution. To make the action potentials or trains of action potentials comparable, the membrane potential was maintained at approximately – 80 mV in current clamp experiments by injecting sustained depolarizing or hyperpolarizing currents through the recording electrode. The length of the current pulse was 1 and 10 ms for single action potentials and 500 ms for series of action potentials.
Identification of dorsal horn neurones
Dorsal horn neurones were identified in spinal cord slices as multipolar cells with a soma (8–12 µm diameter) located in laminae I–II. Neurones were distinguished from glial cells in voltage clamp mode on the basis of a procedure described previously.12 In all neurones studied, a large Na+ current exceeding 1 nA could be elicited, action potentials could be generated, and sometimes they showed spontaneous synaptic activity. Resting potentials in intact neurones were measured between – 84 and – 50 mV.
Entire soma isolation (ESI)
Experiments in voltage clamp mode were performed using the method of ESI to reduce series resistance. Identification of a neurone in the spinal cord slice was followed by the isolation procedure. A detailed description of the ESI method has been given elsewhere.12 Briefly, in whole-cell recording mode, the entire soma of the neurone was isolated from the slice by slow withdrawal of the recording pipette. The isolated structure was classified as soma + axon complex if it contained one process and preserved more than 90% of the original Na+ current. The sound physiological condition of an isolated structure was confirmed by a considerable increase in its input resistance (reflecting a decrease in membrane leakage conductance), by stable or even improved membrane resting potentials and by the ability of soma + axon complex to be excitable (i.e. to generate action potentials). In addition, the ESI method provides a possibility to study pharmacological properties of different ion currents in identified neurones under conditions where diffusion of the blocker molecules is not impeded by connective tissue surrounding the neurone.12 15
Statistical analysis and fitting
The present study is based on recordings from 24 intact neurones in the spinal cord slice and 85 isolated somata. Numerical values are given as the mean (standard error of the mean). Parameters obtained from fitting data points are given as mean (standard error).
For each individual recording, the firing frequency was determined as f = (N – 1) x (
T)–1, where N was the number of spikes observed during current injection and T was the time interval between the first and the last spikes in the train.
The normalized current amplitudes in concentration–effect curves were fitted using a non-linear least-squares method with the equation: f(C) = 1 – (1 – RES) x Cn/(Cn + IC50n), where C is the blocker concentration, IC50 is the half-maximal inhibiting concentration, n is the Hill coefficient, and RES is the residual fraction of current that cannot be blocked by clonidine. The steady-state inactivation characteristic was fitted using a standard Boltzmann equation: I/I0 = 1/[1 + exp((E50 – E)/k)], where I is a current measured at a given potential (E), I0 is the maximum current, E50 is the potential at which half-maximal conductance is activated, and k is a steepness factor.
Intergroup differences were assessed by a factorial analysis of variance with post hoc analysis using Fisher's least significant difference test. Student's paired t-test was used to compare the relative amplitudes of Na+ currents at the 30th pulse before and after 1000 µM clonidine (phasic block). P-values < 0.05 were considered significant.
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Action potentials
As clonidine has frequently been added to local anaesthetics at low doses, the effect of 10 µM clonidine on action potentials was investigated. A higher concentration of clonidine related to the IC50 for Na+ currents (700 µM) was selected for a better comparison with other drugs (e.g. local anaesthetics or opioids, which have also been investigated at concentrations related to the IC50 for Na+ currents).13 15 16 Current clamp experiments were performed in intact neurones in the spinal cord slice using external solution in the bath and pipettes filled with high K+-1-solution.
Single action potentials were elicited using 1-ms depolarizing current pulses (Fig. 1 and Table 1). A concentration of 10 µM clonidine had little effect on the shape of a single action potential in all three cell types. In TFNs, the firing threshold was lowered significantly. A higher concentration of clonidine (700 µM) had significant effects on the shape of a single action potential. In all three cell types, the peak amplitude of the action potential was lowered, the width of the action potential (measured at half maximal amplitude) showed a distinct increase, and the maximum positive and negative slope decreased. The firing threshold was lowered in all three cell types, a significant difference could only be observed for TFNs. Hyperpolarizing afterpotentials disappeared at a clonidine concentration of 700 µM. A detailed analysis of different action potential parameters is given in Table 1.
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Series' of action potentials were elicited using a depolarizing current pulse (500 ms) of increasing amplitude. Recording in the control solution was followed by the addition of 10 and 700 µM clonidine (Fig. 2). In SSNs (n = 5), only small effects were observed. These neurones produced only one or two action potentials at the beginning of the depolarizing pulse, and the firing pattern was not changed even at high concentrations of clonidine. In AFNs (n = 5), a concentration of 10 µM clonidine had little effect on the pattern of action potentials. After application of 700 µM clonidine, the number of action potentials was reduced from 3.6(0.2) in the control solution to 1.6(0.4) in the presence of clonidine. The most distinct effect was observed in TFNs (n = 5), even at a concentration of 10 µM clonidine a reduction in firing frequency of 35% [from 29.9(1.7) to 19.3(1.1) Hz] was noted. After application of 700 µM clonidine, the neurones were no longer able to generate series of action potentials. Only a few spikes 2.3(0.8) were found at the beginning of the depolarizing pulse [compared with 14.3(1.4) in control solution].
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Na+ currents
Na+ currents were recorded from isolated somata of different spinal dorsal horn neurones in external TEA-solution using pipettes with CsCl-solution. Externally applied clonidine at concentrations ranging from 30 to 3000 µM reversibly blocked the peak Na+ current in a concentration-dependent manner (Fig. 3A). Each soma was only exposed to a single concentration of clonidine. Figure 4A depicts currents of 36 experiments (nine at each concentration) normalized to control recordings. The concentration–effect curve was fitted with the Hill equation. The corresponding half-maximum inhibiting concentration (IC50) was 707(40) µM. To investigate the use dependence of Na+ current block by clonidine, Na+ currents were activated at frequencies of 2 and 10 Hz in control solution initially and then in the presence of 1000 µM clonidine. The current under control and several consecutive currents recorded at 2 Hz in 1000 µM clonidine are shown in Figure 5A. Figure 5B shows the peak amplitudes of the Na+ currents in control and after addition of 1000 µM clonidine normalized to the amplitude of the first current recorded in control (n = 9). In the absence of clonidine, the amplitude of the 30th current was reduced by 25% probably because of an insufficient recovery of Na+ channels from slow inactivation. In the presence of 1000 µM clonidine, the relative amplitude was reduced from 33% at the first pulse to 23% at the 30th pulse. This corresponds to a current reduction of 30% (not significant). A similar effect could be observed at 10 Hz (not shown; n = 9). In the absence of clonidine the amplitude of the 30th current was reduced by 42% in control solution and by 44% in the presence of 1000 µM clonidine (n.s.). The steady-state inactivation curves of voltage-dependent Na+ currents are shown in Figure 5C (n = 9). Fitting of control data with the Boltzmann equation resulted in an E50 of – 66.4(0.5) mV and k of 8.4(0.4). Application of 30 µM clonidine led to an E50 of – 73.4(0.3) mV and k was 9.1(0.3) (
E50 = 7.0 mV). A more pronounced effect could be observed after application of higher concentrations of clonidine (300 µM, E50 = 7.9 mV and 1000 µM, E50 = 9.6 mV; Fig. 5C; n = 9, respectively).
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) and in the presence of 1 mM clonidine (•) as a function of pulse number. Each current was normalized to the amplitude of the first Na+ current recorded in control solution (n = 9). (C) Inactivation of Na+ currents in control (K+ currents
K+ currents were recorded from isolated somata of spinal dorsal horn neurones in external choline-Cl-solution using pipettes filled with high K+-2-solution (Fig. 3B, C). Clonidine was applied externally at concentrations ranging from 30 to 3000 µM. Each soma was only exposed to a single concentration of clonidine. Fast inactivating KA currents were incompletely blocked by externally applied clonidine. The maximal achievable block was 48%. KDR currents showed a similar sensitivity to clonidine. The maximal achievable block was 55%. Data were not fitted with the Hill equation (n = 49; Fig. 4B).
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In addition to its useful therapeutic effects after systemic application, clonidine is used to amplify and prolong epidural or subarachnoid anaesthesia.3 The mechanism of action of subarachnoid or epidurally applied clonidine must exceed a simple vasoconstrictor effect, as application of 150 µg clonidine to spinal bupivacaine does not decrease circulatory absorption of spinal bupivacaine.17 Furthermore, clonidine produces analgesia as a sole agent, without local anaesthetics or opioids.6
To date, several mechanisms of action are described: (1) interactions with 2-receptors,18 (2) interactions with imidazoline receptors,19 (3) interactions with high-voltage-activated Ca2+ currents,20 and (4) effects on hyperpolarization-activated cation currents.21 The aim of our study was to describe the effects of clonidine on the generation of action potentials in different types of dorsal horn neurones involved in transmission of pain. As the shape of single action potentials was modified by clonidine, a possible interaction with voltage-gated Na+ and K+ currents was investigated.
- In current clamp mode, firing frequency of trains of action potentials in TFNs is reduced at low concentrations (10 µM) of clonidine.
- The shape of single action potentials is modified at high concentrations (700 µM) of clonidine.
- Low concentrations of clonidine (30 µM) shift the steady-state inactivation curve to more negative potentials.
- Voltage-gated Na+ and K+ currents are partially inhibited at clinically relevant (<100 µM) concentrations of clonidine.
Single action potentials are not completely suppressed by the concentrations of clonidine used. Peak, duration, positive, and negative slope of single action potentials are reduced at higher concentrations of clonidine in all three types of neurones investigated. This is because of an incomplete block of voltage-gated ion channels, the effects of clonidine on the shape of single action potentials are most likely mediated by a block of voltage-gated Na+ and K+ currents. This observation confirms results obtained from desheathed rat sciatic nerves22 and could explain the effects of clonidine in the block of action potentials in peripheral nerves where higher concentrations (450 µM)22 of clonidine are applied. Lower concentrations (10 µM) of clonidine, insufficient for suppression of a single action potential, reduced the maximum firing frequency to 65% in TFNs, whereas AFNs and SSNs remained unaffected. Olschewski and colleagues16 observed a reduction in firing frequency to 72% in TFNs after the application of 10 mM tetraethylammonium by blocking approximately 50% of KDR current. A similar reduction in firing frequency (to 68%) was caused by 100 µM droperidol, blocking voltage-gated Na+ and KDR currents to about 50%. An exclusive block of 50% of voltage-gated Na+ currents by 10 nM tetrodotoxin was insufficient to produce a reduction in firing frequency.16 Computer simulation revealed that a balanced contribution of Na+ and KDR currents in TFNs is important for the generation of series of action potentials.23 The additional block of KDR currents with a low safety factor could reduce the firing frequency by moving the critical equilibrium of Na+ and K+ currents.
Clonidine exhibits a tonic blockade of voltage-gated Na+ currents in sensory neurones of laminae I and II of rat spinal cord. The IC50 value for tonic block is 707(40) µM, with a Hill coefficient of 0.99(0.06), suggesting that one blocker molecule interacts with one receptor. This IC50 value is in the range reported for most local anaesthetics14 or meperidine.13 At clinical concentrations, when clonidine was applied intrathecally, only a few (about 10–20%) Na+ channels are blocked. Spinal dorsal horn neurones have a large reserve for Na+ channels and therefore generation of action potentials is not suppressed until four-fifths of the Na+ channels are blocked.16 It is therefore unlikely that the analgesic action of clonidine is effected exclusively by a tonic block of voltage-gated Na+ channels. However, our data illustrate that even 30 µM clonidine shifts the steady-state inactivation curve significantly to more negative potentials indicating an increased affinity of the blocker molecule for the open or inactivated state of Na+ channels. At a given resting potential of – 70 mV, the number of available Na+ channels is reduced to about two-thirds. This effect is more apparent at higher concentrations of clonidine. These results strongly suggest that a concentration-dependent reduction of Na+ channels by clonidine may contribute to the reduction of excitability in all types of dorsal horn neurones. The lack of a significant use-dependent block by clonidine indicates a considerably lower increase in the affinity to the open or inactivated state compared with local anaesthetics14 or meperidine.13
K+ channels play an important role in regulating firing patterns of different neurones. In our experiments, clonidine produced a tonic blocking action on KA and KDR currents. The maximum achievable block of these currents is approximately 50%. The incomplete block of K+ currents has already been observed for local anaesthetics14 or opioids13 and might result from a diversity of K+ channels that generate this current. Although the inhibitory effects of clonidine on KA and KDR currents was less pronounced, the block of K+ currents could become important if these neurones possess small resources of K+ currents. The safety factor for K+ channels is rather low compared with Na+ channels and seems to be lower than 2.16 Therefore, a block of small fractions of K+ currents by clonidine is more likely to affect the generation of different firing patterns in spinal dorsal horn neurones. Additionally, block of KDR by clonidine led to a decrease in the maximum negative slope of the action potential at higher concentration, similar to TEA,16 providing support for the role of KDR channels in spike repolarization. As KA currents in spinal dorsal horn neurones are essentially inactivated at resting potential,24 the block of KDR currents seems to be critical for regulating firing frequency.
When applied intrathecally, the clonidine dose used for anaesthesia varies between 50 and 450 µg.5 6 25–27 Assuming that the volume of distribution after an intrathecal application ranges from 2028 to 50 ml,29 the maximum cerebrospinal fluid (CSF) concentration can be calculated to be 100 µM (400 µg clonidine intrathecally). In a sheep model, using different routes of application Eisenach and collegues30 found a local anaesthetic effect after an intrathecal application of 300 µg clonidine and a volume of distribution of 6.9 ml corresponding to a maximal CSF concentration of 200 µM. After a dose of 1 µg kg–1 intrathecally clonidine in humans, the peak CSF level was about 6 µM.27 These concentrations are within the range required to partially block voltage-gated Na+ and K+ currents and to shift the steady-state inactivation curve to more negative potentials. As the plasma concentrations after intrathecal administration are up to 1000-fold higher27 30 compared with those after i.v. application, it is unlikely that the effects of intrathecal clonidine can be explained by the mechanisms responsible for the effects of systemically applied clonidine such as an interaction with 2- or imidazoline-receptors. As systemic side effects such as hypotension5 6 or sedation5 25 occur during subarachnoid application of clonidine, an additional analgesic effect by a systemic interaction of absorbed clonidine cannot be completely excluded. Because of the different clonidine concentrations after systemic and spinal application, no specific antagonist of clonidine action was investigated in our study.
In conclusion, clonidine at concentrations achieved after intrathecal application suppresses the generation of series of action potentials in TFNs. The generation of action potentials in AFNs and SSNs remains unaffected. As TFNs are either nociceptive-specific or wide-dynamic-range neurones, our results provide insight into the physiological basis for the antinociceptive action of clonidine at the spinal cord level. Part of this action can be explained by an interaction with voltage-gated Na+ and K+ channels.
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We thank Dr Rory E. Morty, and PD Dr M. E. Bräu for critically reading the manuscript. Excellent technical assistance by B. Agari and O. Becker is gratefully acknowledged. The study was supported in part by the Deutsche Forschungsgemeinschaft (Vo 188/21-2) and by the Justus-Liebig University, Giessen, Germany.
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References |
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