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Department of Neurosurgery, Experimental Neurosurgery, University Hospital Aachen, D-52074 Aachen, Germany
Submitted 17 February 2004; accepted in final form 18 April 2004
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ABSTRACT |
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1 h after the end of conditioning stimulation. After additional high-frequency stimulation, the reflex partly recovered from LTD. High-frequency stimulation alone induced a transient increase of the JOR integral for <10 min. The LTD of the sensorimotor jaw-opening reflex in anesthetized mice may be an appropriate model to investigate the central mechanisms and the pharmacology of synaptic plasticity in the orofacial region. The application of electrophysiological techniques in mice provides the opportunity to include adequate knock-out models to elucidate the neurobiology of LTD. |
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INTRODUCTION |
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; Kemp and Bashir 2001). LTD is regarded as one main experimental model for learning and memory processing in the mammalian brain. LTD has been investigated for the somatosensory system on the level of the secondary sensory neuron in slice preparations. In rat spinal cord slice with a long dorsal root attached, substantia gelatinosa neurons were intracellularly recorded (Randic et al. 1993; Sandkühler et al. 1997). Electric low-frequency stimulation (LFS) of the dorsal root produced a robust LTD (Sandkühler et al. 1997). The effect was also documented by an optical imaging method (Ikeda et al. 1999). Brief high-frequency electric stimulation (HFS) induced LTD in 41% of sensory spinal neurons in laminae I–III (Randic et al. 1993). In a similar model, HFS caused LTD in 54% of spinal neurons in laminae III–IV (Garraway and Hochman 2001). Thus conditioning electric stimulation induced LTD of synaptic transmission in spinal layers I–IV that are involved in somatosensory processing. So far, it is unknown whether the results in the spinal dorsal horn can be applied to the medullary dorsal horn (Bereiter et al. 2000).
Although LTD could be reliably induced in vitro, inconsistent results were soon encountered when the same types of experiments were conducted in adult animals in vivo (Bear 1999; Braunewell and Manahan-Vaughan 2001). Therefore the significance of LTD for memory processes has been questioned due to reported failures to induce persistent LTD in vivo. LTD of spinal somatosensory processing has been investigated under in vivo conditions in only one paper (Liu et al. 1998). Spinal field potentials were evoked by sciatic nerve stimulation in anesthetized adult rats. Electric LFS induced LTD in only 2 of 11 rats.
The present study addressed the hypothesis that LTD of orofacial sensorimotor processing can be induced in mice under general anesthesia. The effects of electric LFS and HFS of the tongue on the jaw-opening reflex (JOR) elicited by electric tongue stimulation were investigated.
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METHODS |
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12 wk old; 20–27 g). All procedures received institutional approval from the local ethics committees of the university of Erlangen-Nuremberg (No. 621–2531.31-15/01) and the university of Aachen (No. 50.203.2-AC 15, 16/03). The principles of laboratory animal care and use of laboratory animals [European Communities Council Directive of November 24, 1986 (86/609/EEC)] were followed. All efforts were made to minimize animal suffering and to use only the number of animals necessary to produce reliable scientific data.
The detailed description of anesthesia, surgery, and electrophysiological recording in mice recently has been published (Ellrich and Wesselak 2003). The mice were anesthetized by an initial intraperitoneal injection of a 0.5% pentobarbital sodium salt (Sigma-Aldrich, Germany) solution with a dose of 70 mg/kg. Depth of anesthesia was checked by ensuring that noxious pinch stimulation (blunt forceps) of the hind paw, the forepaw, and the ear did not evoke any sensorimotor reflexes. When the mouse was sufficiently deeply anesthetized, the skin of the throat was carefully shaved and lidocaine gel (Xylocain gel, AstraZeneca) was applied to induce local anesthesia. Dexpanthenol eye ointment (Roche) was applied to the cornea of both eyes to protect it from drying. The left external jugular vein was catheterized for continuous administration of a 1% methohexital sodium salt solution with a dose of 60 mg · kg–1 · h–1 corresponding to a flow rate of 0.15 ml/h for a 25-g mouse. A pair of Teflon-coated stainless steel wires (140 µm diam) was inserted into the right anterior digastric muscle (Dig) to record electromyographic (EMG) activity via a differential amplifier. After tracheotomy, animals were placed in a stereotaxic frame and were artificially respired with a stroke volume of 0.5 ml and 180 strokes/min for the duration of the experiment. The body core temperature was maintained at 37.5°C with a heating blanket and a fine rectal thermal probe (FMI). One platinum needle electrode each (300 µm diam) was subcutaneously inserted into the left forepaw and the right hind paw to record the electrocardiogram (ECG) via a differential amplifier. Two stainless steel needle electrodes (150 µm diam) were longitudinally inserted into the tongue musculature (parallel, 2 mm distance) to apply electric stimuli. Electric test stimulation to evoke the JOR and electric LFS and HFS were applied by the same intramuscular tongue electrodes. The oral cavity was filled up with white petroleum jelly (Vaseline; Riemser) to protect the oral mucous membrane from drying. After the surgery and the placement of all electrodes the anesthetized animal had a rest for 1 h. In this time period the level of anesthesia (reflexes) and the heart rate were routinely checked and documented.
All electric signals (EMG, ECG) were recorded by bioamplifiers and led into a data collection system (CED micro 1401) and a personal computer to compile waveform files using the Signal software program (CED, Cambridge, UK).
The JOR was elicited by rectangular electric pulses of 500-µs duration with a stimulation frequency of 0.1 Hz. The electric threshold of the JOR was determined by applying increasing and decreasing stimulus intensities from 0 to 2 mA in steps of 100 µA. The lowest stimulus intensity that just evoked a reflex response was defined as the JOR threshold (IJOR). The test stimulus intensity was adjusted to 1.5 or 4 times the IJOR. The JOR was evoked in blocks of five stimuli each. These blocks were repeated every 5 min. After the three baseline JOR blocks, either conditioning electric stimuli were applied (LFS, HFS) or the block stimulations suspended for 10 min (no stimulation). After the conditioning stimulation or the no stimulation period, the JOR blocks were repeated every 5 min for 1 h. Conditioning LFS and HFS and test stimuli were administered by the same needle electrodes in the tongue. LFS consisted of 1,200 rectangular pulses (500-µs pulse duration) applied with a frequency of 1 Hz and stimulus intensities of 1.5 or 4 times the IJOR (LFS 1.5, LFS 4.0). HFS consisted of 10 trains of 100 rectangular pulses (500-µs pulse duration) each with a frequency of 100 Hz repeated every 10 s applying stimulus intensities of 1.5 or 4 times the IJOR (HFS 1.5, HFS 4.0). In some experiments, HFS was additionally applied after the finish of the LFS session.
Onset and end of each single JOR sweep were manually marked by cursors applying the Signal software. EMG recordings did not show any spontaneous activity of the digastric muscle, and reflex activity was always well-defined. Duration and integral of the JOR were calculated in the time window between onset and end of the reflex in each single sweep by the Signal software. Arithmetic mean ± SE was calculated. One- and two-way repeated-measures analyses of variance were applied to test statistically significant differences within and among groups (LFS 1.5, LFS 4.0, HFS 1.5, HFS 4.0, no stimulation). Multiple comparison procedures were performed by the Holm-Sidak post hoc test.
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RESULTS |
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2 mA, the integral and the duration increased, whereas the onset latency decreased. Stimulus intensities (IS) were adjusted either to 1.5-fold the IJOR (n = 24: IJOR = 398 ± 29 µA, IS = 597 ± 43 µA) or to 4-fold the IJOR (n = 16: IJOR = 350 ± 31 µA, IS = 1,400 ± 122 µA). In the control experiments, 15 blocks of five sweeps each of the JOR were recorded applying a stimulus intensity of 1.5-fold the IJOR in eight experiments. The one-way repeated-measures ANOVA (factor:time) documented a reduction of onset latency (F = 2.418, P < 0.01), whereas integral (F = 0.28) and duration (F = 1.314) remained unchanged. The Holm-Sidak post hoc test explained the significant decrease of onset latency by statistical differences between the low onset latencies at the time points 45 (–3.1%), 55 (–3.3%), and 60 min (–3.7%) in comparison to the latencies at the time points –15, –10-, –5, 5, 15, 20, and 25 min (P < 0.05).
In the LFS experiments, a period of conditioning LFS of the tongue with a frequency of 1 Hz and duration of 20 min followed the 3 baseline blocks and preceded the 12 blocks that were recorded within 1 h after the end of LFS (Fig. 1). Test and conditioning LFS stimulus intensities were adjusted to either 1.5- or 4-fold the IJOR in eight experiments each (LFS 1.5, 4.0). The two-way repeated-measures ANOVA (factors: kind of conditioning stimulation, time) for the control experiments without any conditioning stimulation and the LFS experiments (LFS 1.5, 4.0) showed a statistically significant difference in the mean JOR integrals among the different stimulation conditions (F = 20.157, P < 0.001). Furthermore, there was a significant interaction between the stimulation factor and the time factor (F = 1.832, P < 0.05). The Holm-Sidak post hoc test found significantly decreased integrals in the LFS experiments as compared with the control session (P < 0.001). Onset latency and duration data did not statistically differ among the control, the LFS 1.5, and the LFS 4.0 groups. In the LFS 1.5 experiments, integral decreased by 43.0 ± 3.4% (F = 13.033, P < 0.001), duration decreased by 7.1 ± 1.7% (F = 3.582, P < 0.001), and onset latency increased by 2.4 ± 0.8% (F = 3.935, P < 0.001) within 1 h after the end of LFS (Fig. 1). Whereas the Holm-Sidak post hoc test explained the changes of the integral by significant differences between the baseline data and all post-LFS blocks (P < 0.001), the changes of JOR duration and onset latency were mainly due to significant effects at the time points 5 and 10 min after the end of LFS as compared with all baseline data (P < 0.05). After LFS 4.0, the integral and the duration of the JOR significantly decreased by 53.4 ± 1.0% (F = 23.393, P < 0.001) and 15.0 ± 1.2% (F = 2.224, P < 0.012), respectively. All integrals of the JOR after conditioning LFS were significantly smaller than the reflexes of the three baseline blocks (Holm-Sidak, P < 0.001). The significant reduction of the JOR duration was mainly due to differences between the baseline reflexes and the JOR at the time points after 35 min (Holm-Sidak, P < 0.001). Onset latency remained unchanged according to the one-way repeated-measures ANOVA. In six of eight LFS 1.5 experiments, HFS was additionally applied after the end of the LFS experiment. After additional HFS, onset latency, duration, and integral of the JOR significantly changed to a level of –4 ± 0.4% (F = 7.084, P < 0.001), 7.7 ± 1.8% (F = 7.918, P < 0.001), and 20.6 ± 13.5% (F = 7.813, P < 0.001), respectively, within 15 min after the end of HFS. In seven of eight LFS 4.0 experiments, an additional HFS significantly changed onset latency, duration and integral to a level of –3 ± 0.8% (F = 7.128, P < 0.001), 2 ± 2% (F = 5.768, P < 0.001), and –4.3 ± 10% (F = 14.404, P < 0.001), respectively, within 15 min after the end of HFS. Thus additional HFS significantly changed the depressed JOR. Especially in the LFS 4.0 group, additional HFS caused a partial recovery from JOR depression to levels of latency, duration, and integral which were very similar to the baseline parameters (before any conditioning).
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DISCUSSION |
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1 h in mice. With stimulus intensities of 1.5 and 4 times the reflex threshold, the JOR integral decreased on average by 43 and 53%, respectively.
The JOR is a trigemino-trigeminal brain stem reflex that can be elicited by electric, thermal, and mechanical stimulation of the orofacial region (Chiang et al. 1991; Ellrich et al. 2001; Gear et al. 1999; Takeda et al. 1998; Ulucan et al. 2003). Trigeminal afferents synapse on sensory neurons of the spinal trigeminal complex. These neurons bilaterally project to excite digastric motoneurons (Kidokoro et al. 1968; Tsai et al. 1999). Thus at least two synapses are involved in the reflex arc. With 600 µA (1.5 times IJOR) and 1,400 µA (4 times IJOR), the applied electric test and conditioning stimuli caused a pricking painful sensation in man indicating an excitation of thin-myelinated, nociceptive group III muscle afferents corresponding to A
-fibers (Bromm and Meier 1984; Kaube et al. 2000). In muscle nerves of the cat, group IV afferents were assumed to be activated by electric stimuli with intensities of 10 times the nerve threshold (Lundberg et al. 1987; Steffens and Schomburg 1993). Electric stimulation of dorsal roots in spinal cord slices evoked C-fiber potentials only with intensities corresponding to about ninefold the A-fiber threshold (Sandkühler et al. 1997). In microelectrode studies in human nerves, C-fiber activity could only be evoked by electric stimuli with intensities of 15–20 times the detection threshold (Burke et al. 1975). Thus stimulus intensities of 1.5–4 times the JOR threshold do probably not excite any group IV muscle afferent or C-fiber. The JOR is under strong descending modulatory control from the periaqueductal gray, the nucleus raphe magnus, and many other brain areas (Belforte et al. 2001; Chiang et al. 1990, 1991; Ellrich and Wesselak 2003; Inoue et al. 2001; Kowada et al. 1991; Olsson and Landgren 1980; Zhang et al. 1999). The JOR seems to be an adequate model to investigate A-fiber mediated long-term depressive effects on somatosensory and sensorimotor processing.
The sustained depression of the JOR may be due to an inhibitory effect on synaptic transmission at the first sensory synapse in the spinal trigeminal complex (Kidokoro et al. 1968). This mechanism would correspond to LTD effects of electric conditioning stimulation of spinal afferents on neurons in the spinal dorsal horn in vitro (Garraway and Hochman 2001; Randic et al. 1993). Alternatively, a depressive effect may also have been established on the synapse between the axon of the secondary sensory neuron and the digastric motoneuron. A further effect on descending modulatory systems of the JOR is also conceivable. One could argue that the conditioning stimulation inducing an LTD of the JOR might reflect a damage of the recorded tissue. This can be excluded because the JOR partly recovered from LTD by additional HFS.
In rat spinal cord slice, amplitudes of excitatory postsynaptic potentials (EPSP) of nociceptive neurons decreased after low-intensity LFS by 43% (Sandkühler et al. 1997). The amount of LTD in deep spinal dorsal horn neurons in vitro was 54% (Garraway et al. 1997). The only study on LTD of spinal nociceptive processing in anesthetized rats showed a reduction of C-fiber evoked field potentials by 41% after noxious HFS (Liu et al. 1998). The magnitudes of LTD in spinal dorsal horn synapses were similar to effects in the present study.
Whereas LFS induced LTD of the JOR in the present study, HFS did not induce a lasting potentiation but only a transient facilitation of the JOR for <10 min. This may be due to the stimulus intensity. In anesthetized rats, field potentials in the spinal dorsal horn were evoked by electric stimulation of the sciatic nerve (Liu and Sandkühler 1997). High-intensity HFS of A- and C-fibers induced LTP in all rats. In contrast, low-intensity HFS of A-fibers without any C-fiber activation never induced LTP. Thus a sufficient excitation of C-fibers is essential for an induction of LTP at nociceptive synapses. With stimulus intensities of 1.5 and 4 times the reflex threshold in the present study, the reflex was mediated by A-fibers; a C-fiber activation can be excluded (see preceding text). Furthermore, the age of the laboratory mice may account for the lack of LTP. Whereas in deep dorsal horn cells LTD could be induced in young and older rats in vitro, LTP could only be induced in young animals (postnatal days 3–6) (Garraway et al. 1997).
Recently, LTD was demonstrated in healthy human beings by electrophysiological means. The electrically evoked blink reflex significantly decreased after painful LFS of cutaneous afferents of the forehead by 50% for 1 h (Schorr and Ellrich 2002). The habituation behavior of the blink reflex increased after LFS. LTD has also been shown for the human masseter inhibitory reflex. Noxious LFS of mental nerve afferents caused inhibition of early and late suppression periods (Ellrich and Schorr 2002). Whereas latency, duration, and integral of the late reflex were strongly modulated after LFS, only the integral of the early reflex significantly changed. In a psychophysiological study, the effects of electric conditioning stimulation on pain perception on the forearm were investigated (Nilsson et al. 2003). Six to 10 min of stimulation induced inhibition of heat and pinch-evoked pain with a partial recovery to baseline values within 1 h. Cortical potentials evoked by electric noxious stimulation of supraorbital nerve afferents significantly decreased by noxious electric LFS in man (Ellrich and Schorr 2004). The stronger habituation of the blink reflex and the different effects of LFS on early and late masseter inhibitory reflexes can hardly be explained by a purely peripheral effect of LFS on the first sensory synapse within the medullary dorsal horn as suggested by in vitro cell studies (Braunewell and Manahan-Vaughan 2001; Kemp and Bashir 2001). LTD of spinal field potentials could be switched to LTP after spinalization (Liu et al. 1998). LTD in the spinal dorsal horn was blocked by µ-opioid receptor antagonists (Zhong and Randic 1996). Local administration of serotonin increased the incidence of primary afferent-evoked LTD in rat deep dorsal horn neurons (Garraway and Hochman 2001). Thus descending modulatory systems seem to be involved in the control of both the induction and direction of evoked synaptic plasticity. The time course of JOR depression after LFS with an early effect of about –80% and a partial recovery to a level of about –40% may be due to an activation of an endogenous (possibly descending) inhibitory control system and an additional activation of a facilitatory mechanism that partially antagonizes the inhibitory control. These opponent mechanisms have been suggested from experiments that demonstrated evidence for a tonically active anti-opioid system (King et al. 2001). The JOR seems to be an appropriate model to investigate these mechanisms because this reflex is under strong descending modulatory control (see preceding text). Especially the descending inhibition of the JOR from the periaqueductal gray and the nucleus raphe magnus is mediated by opioids and may be under the control of tonically active anti-opioid systems (King et al. 2001; Oliveras et al. 1977; Sessle et al. 1981).
LTD of the sensorimotor JOR in anesthetized mice may be an appropriate model to investigate central mechanisms and pharmacology of synaptic plasticity in the orofacial region. The application of electrophysiological techniques in mice may provide the opportunity to include adequate knock-out models to elucidate the neurobiology of LTD.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Ellrich, Dept. of Neurosurgery, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany (E-mail: jellrich{at}ukaachen.de).
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ABSTRACT
INTRODUCTION
