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Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Sherman, Stephen E., Lei Luo, and Jonathan O. Dostrovsky. Spinal strychnine alters response properties of nociceptive-specific neurons in rat medial thalamus. J. Neurophysiol. 78: 628-637, 1997. Experiments in both conscious and anesthetized animals indicate that intrathecal (i.t.) strychnine (STR; glycine receptor antagonist) produces acute, reversible allodynia, as evidenced by inappropriate behavioral and autonomic responses to cutaneous tactile stimuli. Although STR is known to produce disinhibition of afferent input to the spinal cord, changes in spinal reflexes cannot fully explain the complex behaviors observed following i.t. STR. Which supraspinal sites are involved in STR-dependent allodynia and how this abnormal somatosensory message is relayed to these sites remain to be determined. The medial thalamus contains many nociceptive-specific (NS) neurons and is believed to be involved in mediating the affective-motivational aspects of pain. It is thus important to determine whether spinally administered STR elicits changes in the responses of medial thalamic NS neurons. Extracellular single-unit recordings were conducted in urethan-anesthetized rats (290-490 g). A detailed characterization of 20 thalamic NS units (1 per rat; 2 in 1 case) was conducted before and immediately after i.t. STR (40 µg). Initially, all of the units in this study were classified as NS, because they were excited by noxious pinch but not by innocuous tactile stimuli. After i.t. STR, all (formerly NS) units exhibited significant responses to innocuous tactile stimuli (brush and/or air jet) applied to lumbar or sacral dermatomes. This effect of STR on thalamic NS neurons was acute and reversible. The majority of units (11 of 20) also exhibited an increase in spontaneous firing rate. Although the complete pinch receptive field (RF) could not be determined for all units, the available data indicate that the RFs for brush stimulation after i.t. STR were substantially different from the pre-STR pinch RFs for all but three units. The same i.t. STR injection that caused the observed changes in medial thalamus also produced allodynia, in the form of brush-evoked cardiovascular or motor responses, in 18 of the 19 rats. The ability of NS cells in medial thalamus to respond to tactile input after i.t. STR suggests that the STR lowers the threshold of nociceptive neurons that project directly and/or indirectly to medial thalamus. These observations suggest that ascending nociceptive pathways and medial thalamic structures contribute to the expression of STR-dependent allodynia.
Allodynia is a rare but distressing symptom of neural injury or neuropathy that is characterized by the inappropriate perception of light tactile stimuli as being painful. This clinical condition has been modeled experimentally in animals by the spinal administration of strychnine (STR), a glycine receptor antagonist. Under normal circumstances, lightly touching or stroking the hair of a conscious rat or mouse elicits no more than an orientation response. However, after intrathecal (i.t.) STR, an identical tactile stimulus evokes vigorous scratching and biting of the stimulation site, vocalization, attempts to escape, and aggressive behavior (Beyer et al. 1985 Animals
Male Wistar rats (Charles River, St.-Constant, Canada) weighing 290-490 g at the time of the experiment were used for all procedures. Animals were housed in an animal care facility with a 12-h light:dark cycle (lights on at 0700 h) and free access to rat chow and tap water. All experiments were conducted in accordance with the Guidelines of the Canadian Council on Animal Care and were approved by the University of Toronto Animal Care Committee.
Implantation of i.t. catheters
Rats were fitted with i.t. catheters prepared from stretched polyethylene tubing (PE-10). General anesthesia for this procedure was provided by either halothane (1-3% in oxygen; Fluothane; Wyeth-Ayerst Canada) or methohexital sodium (Brietal; 70 mg/kg ip). As previously described (Sherman et al. 1987 Testing of i.t. catheters
After recovery from surgery, but Acute anesthetized animal preparation
On the day of the experiment, surgical anesthesia was induced with halothane, the left jugular vein was cannulated, and anesthesia was maintained with intravenous ethyl carbamate (urethan; 10% wt/vol in saline; Sigma Chemical, St. Louis, MO). The initial urethan dose (1.1 g/kg) was infused slowly over 5-10 min as the effect of halothane declined. Throughout the experiment, anesthesia was supplemented with intravenous urethan as required. A tracheal tube was implanted in all animals and most (14 of 19) had the left carotid artery cannulated for continuous monitoring of blood pressure. Instantaneous heart rate (HR) was derived from the blood pressure tracing off-line with the use of a computer program. Body temperature was maintained at 37°C with the use of a thermostatically regulated heating blanket and a colonic probe. Atropine (0.5-1.0 mg/kg ip; Ormond Veterinary Supply) was administered to reduce respiratory secretions. All incisions and contact points with the stereotaxic frame were infiltrated with 2% lidocaine to reduce basal sensory input.
Extracellular single-unit recordings
The animal was placed in a stereotaxic frame, a craniotomy (~3 × 4 mm) was performed over the sagittal suture in the region overlying thalamus, and the dura mater was removed from the exposed region of cortex (except directly over the midsagittal sinus). With a few exceptions (see RESULTS), thalamic recordings were conducted contralateral to the site of the i.t. catheter as determined by i.t. lidocaine injection.
Assessment of the effects of i.t. STR
i.t. saline was not given routinely as a control for i.t. STR, because the risk of "losing" a single unit was increased by handling the short segment of i.t. catheter just behind the recording site. However, saline injections (15 µl i.t.) did not have any effect on unit responses when tested in a small group of animals and never produced any allodynia-like responses when tested in several previous studies (Sherman and Loomis 1994 Identification of recording sites
On completion of the experiment, an electrolytic lesion was made at the recording site by applying an anodal current of 10-15 µA for ~15 s. The animal was then deeply anesthetized with urethan and perfused transcardially with normal saline followed by 10% Formalin (~200 ml of each). Brains were postfixed in 10% Formalin for Data analysis
For each unit, the mean spontaneous firing rate was calculated over the 20-s interval immediately preceding each cutaneous stimulation. Responses to cutaneous stimuli were considered significant if two or more consecutive 1-s bins in the event histogram exceeded the prestimulus mean firing rate by >2 SD. The mean spontaneous firing rates are depicted as solid horizontal lines on the event histograms; the 2-SD cutoffs are depicted as dashed lines.
The effects of i.t. STR were determined on 20 medial thalamic units in 19 animals. Only one unit was studied in each animal, with the exception of one experiment in which two units were recorded simultaneously and later discriminated off-line. All of the units in this study were classified as NS because they were excited by noxious pinch applied to cutaneous sites, but not by innocuous tactile stimuli. The response properties of all the units tested were affected by i.t. STR.
Effects of i.t. STR on neuronal properties
After i.t. STR, all (formerly NS) units exhibited significant responses to innocuous tactile stimuli (brush or air jet) applied to lumbar or sacral dermatomes. The response properties of a typical NS unit in medial thalamus are outlined in Fig. 2. This unit responded exclusively to noxious pinch applied to either the tail or contralateral hind paw. Innocuous brush or air jet had no effect on HR, blood pressure, or unit firing rate. In contrast, 2 min after 40 µg i.t. STR, similar brush or air jet stimuli evoked a pressor response, tachycardia, motor withdrawal reflexes, and a significant increase in the firing rate of the cell. An example of a response to air jet stimulation is shown in Fig. 2E; the novel RF for brush stimulation is depicted in Fig. 2F. Note that after i.t. STR, the air jet stimulus evoked a prolonged unit response with an afterdischarge (Fig. 2E), similar to the response observed with hind paw pinch (Fig. 2A).
STR-dependent allodynia
Evidence of STR-dependent allodynia, in the form of brush-evoked cardiovascular or motor responses, was observed in 18 of the 19 rats. Blood pressure and HR were monitored in 14 of the 18 animals, but 1 animal that received a higher dose of i.t. STR (50 µg) was omitted from the mean data. In the control period, before administration of i.t. STR, virtually no changes in MAP or HR were observed as a result of brush stimulation (Fig. 6). However, after i.t. STR, a similar brush stimulation evoked tachycardia and significant changes in MAP. Evoked changes in HR followed a consistent pattern with each stimulation; tachycardia appeared abruptly the first time a sensitive dermatome was stimulated and persisted beyond the termination of the stimulus (e.g., Figs. 2 and 3). Changes in MAP were more variable. They were often biphasic, with an initial fall and subsequent rise, but in some instances only a fall or rise was observed. The maximum changes in HR and MAP evoked by brush stimulation are shown in Fig. 6.
STR-dependent allodynia is associated with changes in the responses of medial thalamic neurons
The present study is the first to demonstrate changes in nociceptive neurons concurrently with overt signs of i.t.-STR-dependent allodynia. All of the medial thalamic units examined in the current experiments could only be activated by nociceptive stimuli, except immediately after i.t. STR, when they all developed responsiveness to low-threshold brush or air jet stimulation. Because there is strong evidence that the direct receptor-mediated actions of i.t. STR occur locally at the spinal level (see below), the current results indicate that STR-induced changes at the spinal level give rise to major changes in neuronal properties at the level of the medial thalamus and therefore presumably also at the cortical level. Thus i.t. STR does not simply modify the afferent (or efferent) components of spinal reflex arcs, but also results in altered responses of medial thalamic neurons. This study also shows that spinal application of STR at doses and by the route of administration known to produce behavioral indexes of allodynia produces major changes in the spinal neurons that give rise to ascending pathways influencing medial thalamus. These data provide support for the growing realization of the importance of glycine in the control of nociceptive transmission and for disruption of the normal functioning of this system as a mechanism underlying the development of some types of neuropathic pain. Recent studies have also implicated Evidence for a spinal site of action of i.t. STR
Behavioral observations indicate that the STR-induced disinhibition observed at the spinal level is not generalized to the entire CNS, but rather is a specific effect of STR on spinal segments near the i.t. drug delivery site. The most pronounced unit responses to brush in the current study were evoked from cutaneous sites ipsilateral to the i.t. catheter (as determined by the lidocaine test) regardless of whether these regions were ipsilateral or contralateral to the thalamic recording site. In accordance with these observations, a previous study (Sherman and Loomis 1995 Mechanisms underlying alterations of medial thalamic neuron responses
Because the direct actions of i.t. STR occur at the spinal level (see above), the changes observed in medial thalamus must be due to alterations in the ascending inputs to these neurons. All of the neurons in our study were of the NS type, suggesting that they received either direct or indirect inputs from NS spinal neurons. However, it is also possible that these thalamic NS neurons received inputs originating from WDR spinal neurons, or even possibly from some low-threshold mechanoreceptive neurons, but that these low-threshold afferent inputs were not powerful enough to produce changes in firing rate. If i.t. STR caused spinal NS neurons to start responding to low-threshold inputs and/or caused increased firing of WDR and low-threshold mechanoreceptive neurons to low-threshold tactile inputs, this would explain the lowering in threshold of the NS neurons observed in our study. There are indeed data from spinal cord studies suggesting that STR can produce these types of changes in spinal dorsal horn neurons. For example, previous studies have demonstrated that NS units have subliminal input from low-threshold afferents and that these can be unmasked by STR (Woolf and King 1990 Allodynia
The onset, duration, and quality of allodynia observed in the present experiments were consistent with previous reports of this phenomenon (Sherman and Loomis 1994 Conclusions
In the current study we investigated the effects of i.t. STR on the response properties of NS neurons in medial thalamus. After i.t. STR, neurons that were initially NS became responsive to brush stimulation. The ability of NS cells in medial thalamus to respond to tactile input after i.t. STR indicates that the direct actions of STR on spinal neurons are reflected supraspinally by changes in nociceptive processing in medial thalamus. These data provide strong support for recent studies suggesting that low-threshold inputs can produce pain via central mechanisms under some abnormal conditions and also suggest that medial thalamic structures may play a role in mediating STR-dependent allodynia. Further studies are required to determine the types of spinal neurons involved in relaying abnormal sensory input to medial thalamus and the specific ascending sensory pathway(s) involved.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
, 1988; Onaka et al. 1996; Sosnowski and Yaksh 1989; Yaksh 1989). All of these behavioral responses are usually elicited only by high-intensity and potentially tissue-damaging (nociceptive) stimuli, not light touch. Thus the temporary removal of spinal glycinergic inhibition with i.t. STR results in a disturbance of sensation, resembling the allodynia seen in neuropathic pain patients.
-1996; Yaksh 1989). These responses, suggestive of extremely noxious sensory input and elicited exclusively by nociceptive stimuli in control rats (i.e., no STR), are evoked by cutaneous stimuli (not spontaneous), occur in the absence of convulsions, and are only elicited by stimulation of discrete, segmentally localized cutaneous regions near the i.t. STR injection site (brush stimulation does not evoke motor and autonomic responses after similar doses of intravenous STR) (Sherman and Loomis 1994). In view of the allodynia observed in conscious animals, these cardiovascular and motor reflexes have been interpreted as nocifensive, and because of the innocuous nature of the stimuli, as evidence of allodynia (Sherman and Loomis 1994; Yaksh 1989). These observations suggest that low-threshold mechanoreceptive afferent inputs can potentially activate spinal nociceptive neurons to produce nociceptive responses, but that these inputs are inhibited by glycinergic modulation and are thus subliminal under normal circumstances.
evoked windup of WDR and low-threshold neurons with the use of repetitive natural innocuous brush stimulation. The ability of STR to facilitate low-threshold input to spinal neurons is further supported by the observation that microdialysis of STR (1 mM) into the cat dorsal horn led to an enhancement of responses to hair deflection, enlargement of low-threshold receptive fields (RFs), and increased afterdischarges of low-threshold, NS, and WDR neurons (Sorkin and Puig 1996). Similar results were observed in primates, where microdialysis of STR (2 mM) resulted in a significant increase in background activity of spinal WDR and high-threshold neurons, as well as a significant enhancement of unit responses to brush stimulation (Lin et al. 1994). However, it is not clear whether the concentrations of STR used in these studies are comparable with those used in the behavioral studies, and there was no possibility of correlating the observed neural changes with simultaneous behavior or nociceptive reflexes indicative of allodynia. One of the aims of the present study was to examine the effects of i.t. STR on nociceptive neurons under the same conditions present in previous studies of STR-dependent allodynia (Sherman and Loomis 1994-1996) and also to be able to correlate the observed changes in neural responses with nociceptive cardiovascular and motor reflexes.
. These experiments provide information about supraspinal sites that may participate in the abnormal somatosensory processing that underlies allodynia. A portion of this work has already been presented as an abstract (Sherman et al. 1996).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
), the catheters were filled with sterile saline, inserted through the cisterna magna into the spinal subarachnoid space, and guided 8.5 cm caudally (L1 termination). The rostral 3-5 cm of the catheter was threaded through the skin on the back of the neck and sealed with a stainless steel plug. Animals were permitted to recover for 
3 days after surgery, and only those without signs of neurological impairment were used in the experiments. All animals received a single injection of buprenorphine (Temgesic; 0.3 mg/kg sc) at the time of surgery. Chlorhexidine acetate cream (Hibitane; Ayerst Laboratories, Montreal, Canada; antibacterial/antifungal) was applied daily to the incision for the next 3 days.
24 h before the acute experiment, the patency of the i.t. catheter and its approximate position in the subarachnoid space were tested with the use of an i.t. injection of lidocaine. All animals received 7 µl of preservative-free, sterile 5% lidocaine hydrochloride (Xylocaine Spinal, AstraPharma) flushed through the i.t. catheter with 10 µl of sterile saline. Animals that failed to exhibit signs of brief, reversible, unilateral or bilateral paralysis of the hindlimbs were not used for experimentation.
. Standard extracellular, single-unit recording techniques were employed. Action potentials were amplified, isolated with a dual window discriminator, and observed on an oscilloscope. Unit firing rate and blood pressure were digitized and monitored on-line with a CED 1401 data acquisition system and SPIKE-2 software (Cambridge Electronic Design). A digital recording device (VB-100-B; Instrutech, Great Neck, NY) was combined with a video cassette recorder for data storage.
1 h (no electrode drift), and have an RF that included cutaneous regions expected to be affected by i.t. STR (i.e., the hindquarters).
, 1990), some medial thalamic neurons exhibit prolonged afterdischarges following a single pinch. When cells like these were encountered, only one or two sites were tested for responses to pinch. In most cases, a crude map of the pinch RF was determined by identifying a few sites that were responsive to pinch as well as a few that were not. After the effects of pinch were determined, brush stimuli were applied in a systematic pattern over the trunk and hindquarters (e.g., Fig. 3). Because all cells studied were NS, this stimulation confirmed the absence of any response to brush.
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FIG. 3.
Example of effects of i.t. STR on medial thalamic unit. Before i.t. STR, innocuous brush or air jet stimuli applied to rat hindquarters or trunk failed to alter heart rate, blood pressure, or unit firing rate (A). After 40 µg i.t. STR (B), similar brush stimulation evoked pressor response, tachycardia, motor withdrawal reflexes, and significant increase in unit firing rate at all sites tested (shading on rat drawing); effects of brushing more rostral sites were not tested. Cardiovascular and motor responses evoked by air jet (not shown) were less dramatic than those evoked by brushing, but unit response (B) was comparable with that evoked by pinch before i.t. STR (A). Recovery from effects of i.t. STR was evident by 22 min after drug injection (C). Solid horizontal lines: mean firing rate of unit before stimulus application. Dashed lines: 2 SD from mean. Location of recording site in mediodorsal central thalamic nucleus is shown as filled circle on schematic diagram of rat brain in cross section (D). Abbreviations as in Fig. 1.
207 kPa) was provided with a regulated supply of compressed air. This stimulus was applied parallel to the surface of hairy skin, and had sufficient force to deflect the pelage for 1-2 cm from the tip of the needle.
-1996).
2 days, cut in 100-µm transverse sections with a freezing microtome, and stained with cresyl violet. The position of the recording site was confirmed by coordinating depth measurements and track locations with histologically recovered lesions. Data from individual experiments were pooled on thalamic transverse sections on the basis of the atlas of Paxinos and Watson (1986).
Because the focus of the current experiment is on responses evoked by cutaneous stimuli, the change in MAP or HR has been reported relative to the immediate prestimulus control (20 s before the stimulus, not pre-STR). More precisely, the maximum HR or MAP observed in the 20 s before stimulus application was subtracted from the maximum value observed during stimulus application. The peak/trough of these difference values was then determined for individual animals before and after i.t. STR. The mean of these peak/trough values (before and after STR) was compared with the use of a paired t-test and is presented in Fig. 6.
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FIG. 6.
Maximum brush-evoked cardiovascular responses before and after i.t. STR. Histograms show mean of greatest rise in heart rate (A) and greatest rise (B) or fall (C) in mean arterial pressure (MAP) evoked by cutaneous brush stimulation. Black bars: mean of peak responses before i.t. STR (40 µg). Gray bars: corresponding values after i.t. STR. Asterisk: significant difference relative to pre-STR condition.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
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FIG. 1.
Drawing of medial thalamus recording sites. Filled circles: recording sites on schematic transverse sections of rat thalamus adapted from atlas of Paxinos and Watson (1986) . All units were classified as nociceptive specific (NS; before drug treatment). For simplicity, rostrocaudal planes from 2 to 2.4 mm caudal to bregma have been included on bregma 
2.3 section; those between 2.4 and 2.8 mm caudal to bregma appear on bregma 2.56 section. Note that 2 units were recorded from single site in anteromedial (AM) nucleus. CL, centrolateral; CM, centromedial; GP, globis pallidus; MDC, mediodorsal central; MDL, mediodorsal lateral; MDM, mediodorsal medial; PC, paracentral; Re, reuniens; Rh, rhomboid; Rt, reticular; Sm, submedius; VM, ventromedial; VL, ventrolateral; VPM, ventroposteromedial; VPL, ventroposterolateral; mt, mammillothalamic tract.
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FIG. 2.
Example of effects of intrathecal (i.t.) strychnine (STR) on NS neuron in medial thalamus. Unit exhibited significant increase in firing rate in response to pinch of contralateral hind paw or tail (C, filled cross), but pinching of ipsilateral hind paw (C, open cross) failed to elicit significant unit response (A). Noxious pinch also elicited blood pressure changes and tachycardia (A). Before i.t. STR, application of innocuous brush or air jet stimuli to rat hindquarters failed to alter heart rate, blood pressure, or unit firing pattern (C and D). In contrast, after 40 µg i.t. STR, similar air jet (E) or brush (F) stimuli evoked pressor response, tachycardia, motor withdrawal reflexes, and significant increase in firing rate of cell. Note afterdischarge following air jet stimulus (E). Receptive field (RF) for brush-evoked unit responses is shown in F. Horizontal lines in event histograms: mean prestimulus firing rate; dashed lines: level of 2 SD above mean. Location of recording site in anteromedial thalamic nucleus is shown on schematic diagram of rat brain in cross section (B).
) have demonstrated that the effects of STR are limited to caudal dermatomes; see Fig. 4]. The magnitude of the unit response was greatest when brush was applied ipsilateral to the i.t. catheter position as determined by the lidocaine test (Fig. 3B). The effects of i.t. STR were completely reversible, and brush stimulation no longer elicited cardiovascular, motor, or unit responses at 22 min post-STR (Fig. 3C).
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FIG. 4.
Changes in sensory modality and RFs of NS neurons in rat medial thalamus. Filled crosses: sites where pinch elicited significant unit response. Open crosses: sites where pinch failed to elicit unit response. After i.t. STR, all of these (formerly NS) neurons were excited by brushing over cutaneous regions indicated by shading. (Note that in some cases shading used to delimit brush RFs is obscured by crosses used to mark pinch stimulation sites. In these cases brush RF was continuous even though shading is interrupted by crosses). Cutaneous RFs contralateral to thalamic recording site are shown on right side of drawings for ease of comparison among drawings (regardless of whether recordings are from left or right thalamus). Position of i.t. catheter in lumbar subarachnoid space (as determined by lidocaine test) was contralateral to thalamic recording site in all but 4 animals (A, F, K, and P). Lidocaine effect was bilateral in 1 animal (E), indicating that i.t. catheter was near midline of spinal cord. Dose of i.t. STR was 40 µg except in cases K and N, which received 60 and 50 µg, respectively. Unit numbers and thalamic recording sites are indicated below respective drawings. Abbreviations as in Fig. 1. Recording site was unknown (Unk) for 3 units.
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FIG. 5.
Example of unit with high spontaneous firing rate after i.t. STR. During pre-STR control period, unit responded exclusively to pinch at 3 of 5 cutaneous sites tested (A), and brush stimulation failed to elicit any effect on unit firing rate (B). At 10 min after i.t. STR (40 µg), brush stimulation evoked significant increase in unit firing rate over large, mostly contralateral RF, as shown on rat drawing (D). At 12 min post STR (D, bottom), paw pinch remained effective in evoking unit response, and elicited more prolonged afterdischarge than during pre-STR period (A). By 16 min post-STR, unit developed high spontaneous firing rate that was not altered significantly by brush or pinch stimuli (E). Cardiovascular parameters were not monitored in this animal, but brush-evoked motor withdrawal reflexes were observed at 3, 6, 10, and 16 min post-STR. All effects of i.t. STR appeared to be reversible, and a few minutes later response properties of unit returned to control condition (F). The recording site in mediodorsal medial nucleus is illustrated in C (for abbreviations see Fig. 1).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
-aminobutyric acid as another important spinal inhibitory transmitter involved in the modulation of nociceptive transmission (Lin et al. 1994; Peng et al. 1996).
) demonstrated that cutaneous regions with abnormal tactile sensitivity, as determined by the ability of hair deflection to evoke motor withdrawal reflexes, were also found ipsilateral to the site of i.t. STR delivery. Temporal changes in cutaneous sensitivity were consistent with a caudal spread of STR in the cerebrospinal fluid following i.t. injection. The abrupt onset of STR-dependent allodynia, and the failure of similar doses of intravenous STR (40-200 µg) to elicit allodynia (Sherman and Loomis 1994), provide further evidence for a specific segmental effect of STR on the spinal cord rather than a more global action on the entire CNS.
). In the cat trigeminal nucleus caudalis, locally infused STR enhanced responses of WDR neurons to both innocuous tap and noxious dental pulp stimulation (Khayyat et al. 1975). In the cat spinal cord, Sorkin and Puig (1996) recently confirmed the ability of STR to enhance responses of spinal WDR neurons to low-threshold input. Those authors reported enhanced responses to hair deflection, enlargement of low-threshold RFs, and an increased afterdischarge following microdialysis of STR (1 mM) into the spinal dorsal horn. In contrast to the study by Khayyat et al. (1975), Sorkin and Puig did not observe significant effects of STR on the responses of WDR neurons to high-threshold stimuli. However, a group of 18 cells (of 26) that were deemed "STR responders" on the basis of their enhanced responsiveness to brush (>30% increase in evoked unit response) included 10 WDR units, six low-threshold cells, and two high-threshold neurons (Sorkin and Puig 1996). Thus STR affected several classes of spinal neurons. It is noteworthy that the two spinal high-threshold units that exhibited responses to brush after STR had "minor low-threshold input to brush (<10% of that evoked by squeeze)" before spinal STR administration (Sorkin and Puig 1996). Microdialysis of STR (2 mM) into the primate spinal dorsal horn resulted in a significant increase in background activity of spinothalamic cells as well as a significant enhancement of unit responses to brush and pinch, but not noxious heat (Lin et al. 1994). STR also reduced periaqueductal-gray-stimulation-induced inhibition of these cells in a dose-dependent manner (Lin et al. 1994). This population of spinothalamic cells could be activated antidromically from contralateral ventroposterolateral thalamic nucleus and consisted of 25 WDR and 2 high-threshold neurons (Lin et al. 1994). Recently, Wilcox et al. (1996) demonstrated the ability of repetitive natural innocuous brush stimulation to cause windup of some rat WDR dorsal horn neurons following iontophoretic STR. Windup usually only occurs with peripheral stimuli that are strong enough to activate nociceptive afferents, and therefore these findings suggest that STR is increasing the effectiveness of low-threshold inputs to WDR cells.
-1996; Yaksh 1989). These experiments were conducted under conditions virtually identical to those of the Sherman and Loomis studies (cited above), facilitating comparison of results between these studies. However, the maximum changes in HR and MAP evoked by brush stimulation were less pronounced in the current study than in earlier reports. For example, Sherman and Loomis (1994) reported maximum evoked increases in HR and MAP of 29 ± 1.1 (SE) bpm and 15 ± 1.0 (SE) mmHg, respectively, when hair deflection was applied to the hindquarters after 40 µg i.t. STR (n = 28). In the present study, the peak brush-evoked increases in HR and MAP were 12.5 ± 2.8 bpm and 8.8 ± 1.6 mmHg (n = 13). These differences may be explained by differences in technique, because the hair deflection stimulus in the Sherman and Loomis (1994) study was applied to the most sensitive site on the hindquarters for 2 min, whereas in the current study the brush RF was mapped by applying stimuli at different sites for only a few seconds. The reduced magnitude of cardiovascular responses was thus a predictable outcome of decreasing the stimulation time (which was necessary for the objectives of the current study) and does not detract from the validity of the results.
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ACKNOWLEDGEMENTS |
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We thank P. Kurdybacha for diligent technical support throughout this project; Dr. John Tsoukatos for guidance with the extracellular recordings and assistance with troubleshooting some technical difficulties; M. Teofilo, who helped with various aspects of this project, including the preparation of the figures for this manuscript; and Dr. Ackerman for the loan of some of the apparatus used for this study.
This study was supported by funding from the National Institute of Dental Research (DE-05404) and the Gifford-Jones and W. Ward Awards.
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FOOTNOTES |
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Address for reprint requests: S. E. Sherman, Dept. of Physiology, Medical Sciences Bldg., University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Received 13 January 1997; accepted in final form 8 April 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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-adrenoceptor agonist oxymetazoline.
Eur. J. Pharmacol.
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S. E. Sherman, L. Luo, and J. O. Dostrovsky Altered Receptive Fields and Sensory Modalities of Rat VPL Thalamic Neurons During Spinal Strychnine-Induced Allodynia J Neurophysiol, November 1, 1997; 78(5): 2296 - 2308. [Abstract] [Full Text] [PDF]
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