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Departments of Anatomy and Physiology and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, California 94143
Submitted 1 October 2003; accepted in final form 26 December 2003
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ABSTRACT |
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INTRODUCTION |
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; Hokfelt et al. 1975; Menetrey et al. 1977). SP and NKA interact preferentially, though not exclusively, with NK1 and NK2 receptors, respectively (see Severini et al. 2002 for review) and are most widely implicated in the transmission of nociceptive messages at the level of the spinal cord (Basbaum 1999; Brown et al. 1995; Cridland and Henry 1988; De Koninck and Henry 1991; Duggan et al. 1988; Frenk et al. 1988; Henry 1976; Hylden and Wilcox 1981; Kuraishi et al. 1989; Tiseo et al. 1990; Yaksh et al. 1980). The circumstances under which SP/NKA modulate nociceptive transmission at the level of the spinal cord are unclear. Many studies of the noxious stimulus conditions that evoke the release of tachykinins have focused on SP and the NK1 receptor (Duggan et al. 1988; Mantyh et al. 1995; McCarson and Goldstein 1991); yet, recent evidence indicates that NKA, which is coreleased with SP from primary afferent nociceptors, can also induce NK1 receptor internalization (Trafton et al. 2001). Unraveling the contributions of SP and NKA to spinal sensory transmission is further complicated by the documented contribution of NK2 receptors to nociceptive processing at the level of the spinal cord (Jia and Seybold 1997; Nagy et al. 1994; Seguin et al. 1995). Pharmacological studies using NK1 and/or NK2 preferring antagonists have been extensively studied, but the results have often proven inconclusive, in part because the drugs either have nonspecific actions (Smith et al. 1994) or fail to penetrate the CNS adequately (Holzer-Petsche and Rordorf-Nikolic 1995). To overcome some of these limitations and to more directly assess the contribution of SP/NKA and the NK1 receptor to nociceptive processing, mice lacking either the NK1 receptor (De Felipe et al. 1998) or the ppt-A gene that encodes these peptides (Cao et al. 1998; Zimmer et al. 1998) have been generated.
Previously, we found that the major deficit in the ppt-A –/– mice was in the appreciation of intense noxious stimuli, under acute stimulus conditions (Cao et al. 1998). These mice showed decreased "pain" behavior in response to intense chemical, mechanical, and thermal noxious stimuli. However, the response to stimuli that were just suprathreshold for evoking nocifensive reflexes was unchanged in the ppt-A –/– mice. Consistent with these observations, we found that the decreased nociceptive mechanical and thermal thresholds (allodynia), symptomatic of tissue and nerve injury conditions, did not differ in wild-type and ppt-A –/– mice. That SP is not essential for nerve injury–induced behavioral hypersensitivity is supported by the finding that mechanical sensitivity was comparable in wild-type and NK1 –/– mice after nerve injury (Martinez-Caro and Laird 2000). This result, however, differs from a report in which NK1 –/– mice exhibit deficits in mechanical, but not thermal, hypersensitivity after nerve injury (Mansikka et al. 2000).
The equivocal changes in sensory thresholds of ppt-A –/– and NK1 –/– mice in the setting of injury suggest that tachykinins are not required for the central sensitization of dorsal horn neurons, which is presumed to contribute to the development of injury-induced allodynia. This interpretation contrasts with the numerous pharmacological studies that indicate that tachykinins (notably SP), in fact, contribute to central sensitization (Urban et al. 1994). For example, the induction of LTP in dorsal horn neurons is associated with an increase of SP (Afrah et al. 2002) and "wind-up" to repeated electrical stimulation is attenuated by administration of NK1 antagonists (Budai and Larson 1996). Wind-up is also reduced in spinal cord neurons of mice lacking the NK1 receptor (Suzuki et al. 2003; Weng et al. 2001). Moreover, rats treated with a toxin conjugate (substance P-saporin) that selectively ablates spinal cord NK1 receptor-expressing neurons in lamina I of the spinal cord fail to manifest the behavioral consequences associated with persistent pain states (Nichols et al. 1999) and neurons located in either superficial or deep dorsal horn lose the capacity to support central sensitization (Khasabov et al. 2002).
In light of the reported differences in the behavioral phenotype of ppt-A and NK1 –/– mice (cf. Cao et al. 1998 and De Felipe et al. 1998), the objective of the present study was 2-fold. First, we sought to determine whether the altered stimulus intensity-response phenotype that is observed behaviorally is reflected in differential responsiveness of dorsal horn neurons in wild-type and ppt-A –/– mice. Second, because central sensitization is presumed to be manifest in nociresponsive neurons, we studied the response properties of wide dynamic range (WDR) neurons in wild-type and ppt-A –/– mice, before and after prolonged chemical activation of primary afferent nociceptors. The deep dorsal horn is well suited for evaluating the phenotype of ppt-A –/– mice because these neurons participate in nociceptive processing (Biella et al. 1997; Coghill et al. 1991, 1993; Cumberbatch et al. 1995; Khasabov et al. 2002; Palecek et al. 1992) and there is evidence for functional NK1 (King et al. 1997a,b) and NK2 (Munro et al. 1993) receptors in this region. Furthermore, the phenotyping of the electrophysiological responses in NK1 –/– mice (Suzuki et al. 2003; Weng et al. 2001) has been carried out at this level, thereby facilitating comparisons between the 2 genotypes. Finally, the documented contribution of NK2 receptors to nociceptive processing at the level of the spinal cord (Jia and Seybold 1997; Nagy et al. 1994; Seguin et al. 1995) and the differential contribution of SP and NKA (Cumberbatch et al. 1995; Sluka et al. 1997; Trafton et al. 2001) underscores the importance of studying mice that lack both SP and NKA.
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METHODS |
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). Mice used in this study were N4 generation backcrossed to a CD-1 background. Wild-type and homozygous null (–/–) littermates were used for breeding. Electrophysiological studies
Male mice (30–45 g; no difference by genotype) were anesthetized with 1.5 g/kg [intraperitoneally (ip)] of 10% urethane. Dexamethasone [0.2 mg, subcutaneously (sc)] and atropine (0.3 mg, sc) were administered to minimize spinal cord swelling and to reduce secretions, respectively. Electrocardiograph leads were attached to the right forelimb and left hindlimb, and the heart rate was monitored to gauge the depth of anesthesia. Heart rate was monitored continuously and supplemental doses of urethane were given (ip) as required to maintain a heart rate of about 9–10 Hz. A laminectomy was performed at vertebral levels T13 to L1, corresponding to spinal segments L4–L5. The mouse was placed into a specialized head holder and the vertebral segments on both sides of the laminectomy were clamped firmly. The dura was retracted and a spinal pool was formed and filled with 37° C saline. Core temperature was monitored continuously and maintained close to 37° C with a circulating hot water pad. Bath temperature was also measured periodically.
All experiments were performed blind to genotype. Mice breathed spontaneously throughout the experiment. A fine-tip (<1 µm) tungsten microelectrode with impedance of 4–5 mohm at 1 kHz (FHC, Brunswick, ME) was lowered into the spinal cord (400–650 µm) and extracellular potentials were recorded, amplified, and filtered using standard electrophysiological techniques. Unit activity was acquired, digitized, and discriminated by computer using Experimenter's Work-bench (Datawave Technologies, Thornton, CO). Continuous stroking of the plantar surface of the ipsilateral hindpaw with a sable-hair brush was used as a search stimulus. Once a neuron was isolated, its amplitude was optimized by moving the electrode in the dorsal–ventral plane. Its baseline activity was recorded for 15 min and its responsiveness to mechanical (brush and pinch) and thermal stimuli was tested over the next 30–45 min. Thermal stimuli were delivered by a 3 x 3-mm copper probe heated and cooled by a 9-W Peltier effect device that had a rate of increase of 2° C/s. Three temperature settings were used (mean = 41, 45, and 49 ± 1° C). Each stimulus was presented for 10 s every 5 min, in an alternating fashion, such that there was a 15-min interstimulus interval for each temperature. The probe was positioned firmly onto the center of the receptive fields and maintained at 35.5° C between the periods of stimulation. Mustard oil (3-isothiocynato-prop-1-ene; Sigma, St. Louis, MO), diluted to 10% with mineral oil, was applied with a paintbrush (
60 µl) to the skin around the tip of the probe. Responses to the noxious chemical stimulus were monitored for 10 min after mustard oil application, which was approximately the maximum duration of spontaneous discharge recorded in our previous studies. The responsiveness of the neurons to thermal stimulation, subsequent to the injury-induced sensitization, was then recorded for at least an additional 60–70 min. Paw thickness was measured with a sensitive, spring-loaded caliper (Mitutoyo, #7309, McMaster-Carr, Los Angeles, CA) before and 2 h after mustard oil application.
Data analysis
Electrophysiological data were acquired from 16 mice and analyzed using software from Datawave Technologies (Longmont, CO). In three mice (1 wild-type, 2–/–), multiunit activity was collected and sorted off-line. All data analysis is based on single-unit activity. Bins of 1 s were used to generate peristimulus time histograms. Thermal stimulus-evoked activity was quantified by examining total spikes/stimulus, peak firing rate/bin during stimulus, initial (0–4 s) and sustained (5–10 s) firing during the stimulus and afterdischarges (15 s poststimulus). Thermal stimulus coding was analyzed by one-way factorial ANOVA (within genotype) or 2-way ANOVA (between genotype, temperature) without or with repeated measures (time, for sensitization), followed by post hoc comparisons where appropriate, using either Statview software version 5.01 (SAS Institute, Cary, NC) or GraphPad Prism (GraphPad Software, San Diego, CA). The slopes of the stimulus–response functions were analyzed by a linear regression of the log-transformed temperatures and firing rate for each individual neuron, followed by a t-test to compare the mean slopes by genotype. Mustard oil–evoked activity was compared by an unpaired t-test. These analyses were performed using GraphPad Prism. Results are expressed as means ± SE.
Histology
To mark the location of the recording site we created a lesion (10 µA for 10s) at the end of each experiment. The mice were then perfused transcardially with 10 ml 0.9% phosphate buffered saline, followed by 20 ml 10% formalin. The lumbar segment of the spinal cord was removed, postfixed in a 30% sucrose-formalin solution. Sections (50 µm) were cut on a freezing microtome, mounted on slides, stained with cresyl violet, dehydrated, and coverslipped.
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RESULTS |
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). The mean depth measurements did not differ between sites that were recovered histologically (508 ± 22 µM) and those that were not (526 ± 22 µM). The neurons were classified as multireceptive based on their responses to innocuous and noxious mechanical and thermal stimuli. We observed no significant difference in spontaneous firing in cells from wild-type (2.4 ± 1.6 Hz; n = 8) and ppt-A –/– (1.8 ± 0.9 Hz; n = 13) mice. Coding of thermal stimuli by lamina V neurons
We characterized the thermal stimulus–response profiles of these neurons by applying thermal stimuli to the plantar surface of the ipsilateral hindpaw. Neurons from both wild-type and ppt-A –/– mice exhibited significant temperature-dependent increases in firing rate [F(1,19) = 4.83; P < 0.05; Fig. 1]. Although we detected a significant interaction by temperature and genotype [F(2,38) = 3.5; P < 0.05], there was no statistical difference in the slopes of the stimulus–response functions (1.6 ± 0.2 and 1.4 ± 0.2 in wild-type and –/– mice, respectively). For the 41, 45, and 49° C settings, the peak temperatures were 43.5, 47.5, and 51.5° C, respectively (Fig. 2, A–C). Neurons from wild-type and ppt-A –/– mice displayed comparable maximal firing rates (26.1 ± 6.1 vs. 25.6 ± 7.5 Hz, respectively) and latencies to peak firing (3.3 ± 0.3 vs. 3.5 ± 0.3 s, respectively). However, in the ppt-A –/– mice, fewer total action potentials were generated in response to sustained temperatures of 41, 45, and 49° C [F(2,38) = 5.2; P < 0.01; Fig. 2] and post hoc analyses revealed that the responses to the 49° C setting were significantly different between wild-type (138.1 ± 33.9) and ppt-A –/– (67.8 ± 14.0) mice (P < 0.05, Fig. 3A).
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Neuronal responses after C-fiber–induced sensitization
To determine the contribution of tachykinin peptides to sustained noxious stimulus-induced activity, we applied the algogenic substance mustard oil (MO) to the plantar surface of the ipsilateral hind paw and recorded the ongoing responses of multireceptive neurons in the deep dorsal horn. We detected no difference in paw thickness 2 h after MO application between wild-type (+1.1 ± 0.1 mm) and ppt-A –/– mice (+1.0 ± 0.1 mm). Mustard oil produced an initial barrage of activity in neurons from both wild-type and ppt-A –/– mice (Fig. 4, A and B, respectively). Neither the mean total number of spikes generated during the 10 min that followed MO application (Fig. 4C) nor the peak firing rate (Fig. 4D) evoked after MO application differed significantly between the genotypes. However, only 2/8 (25%) neurons from the ppt-A –/– mice fired continuously for the 10 min after MO application, compared with 5/6 (83%) neurons from the wild-type mice (cf. Fig. 4, A and B). By comparing spontaneous activity (i.e., before each thermal stimulus presentation), we found increased activity after MO application only in wild-type mice [F(1,11) = 2.6, P < 0.01], which was significantly greater than pre-MO activity only at the 10-min time point (Fig. 5). There was no difference in spontaneous activity between the 2 genotypes over time (Fig. 5).
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DISCUSSION |
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; Toda and Hayashi 1993). We further showed that neurons from both genotypes were sensitized to thermal stimuli applied after mustard oil but, consistent with the findings in the absence of injury, the temporal response profile remained altered in the ppt-A –/– mice. Specifically, poststimulus discharges were significantly reduced in ppt-A –/– mice compared with wild-type mice.
Tachykinins are released both peripherally and centrally where they contribute to both peripheral and central sensitization (Levine et al. 1993). For this reason deficits in sensitization at either locus could account for the absence of sustained stimulus-evoked neuronal activity that we recorded in the ppt-A –/– mice. Many studies have implicated SP and NK1 receptors in spinal cord excitability and central sensitization (Afrah et al. 2002; Dougherty et al. 1993; Khasabov et al. 2002; Laird et al. 2001; Palecek et al. 1992; Xu et al. 1992). However, because we monitored enhanced neuronal responsiveness to stimuli only within, not outside, the receptive field of the neuron, we cannot conclusively state that the observed deficit in ppt-A –/– mice was attributed to impaired central sensitization rather than to a reduction in peripheral sensitization. Although the total number of spikes evoked by mustard oil was not significantly reduced in the ppt-A –/– mice, the patterns of evoked activity differed from those in wild-type mice. In the absence of SP/NKA, fewer neurons fired continuously after MO application. Because MO evokes spontaneous activity in and sensitizes C-fibers (Reeh et al. 1986), it is possible that the reduction in ongoing activity in spinal cord neurons reflects a deficit in SP-induced activation of C-fibers. On the other hand, the similarity in the magnitude of paw swelling between genotypes suggests that at least manifestations of peripheral activation were intact.
Because the inflammation produced by mustard oil should have a neurogenic component that depends on the release of substance P and/or NKA, the absence of reduced inflammation in the ppt-A –/– mice was unexpected. Although we have no firm explanation for this observation, we note several differences between the current study and our previous study (Cao et al. 1998). In wild-type mice, the magnitude of the increase in paw diameter evoked by mustard oil was much greater than that evoked by capsaicin ( 1 mm increase vs. 0.45 mm). This difference may be a function of the different time points at which edema was measured (2 h vs. 30 min), differences in the intrinsic potency of mustard oil and capsaicin at evoking the neurogenic response, the concomitant intermittent application of noxious thermal stimuli, or a combination of these factors. Inoue and colleagues (1997) reported that mustard oil more effectively evoked extravasation in mouse ear within the first 20 min after topical application and that the involvement of the NK1 receptor was limited to the first 5 min. This suggested that other mediators contribute to the inflammatory response at later time points (Inoue et al. 1997). Indeed, the increase in paw thickness after mustard oil and the thermal stimulation paradigm used in this study was 26% greater than that produced by mustard oil alone over the same time course (unpublished observations). This degree of inflammation is comparable to that produced by a nonneurogenic inflammatory stimulus (complete Freund's adjuvant [CFA]) for which we previously showed no difference between wild-type and ppt-A –/– mice. It is possible that this degree of inflammation masked the contribution of SP and/or NKA. Finally, in light of the finding that mustard oil and capsaicin evoked plasma extravasation by distinct mechanisms (Inoue et al. 1997), we cannot rule out the possibility that the SP contribution to the capsaicin-induced inflammatory response is greater than it is to the mustard oil–evoked inflammation. The differential contribution of SP and NK1 receptors to mustard oil– and capsaicin-evoked responses is supported by the finding that NK1 –/– exhibit normal responses to mustard oil, but reduced responses to capsaicin (Laird et al. 2001).
There are several similarities, but also important differences between our results and results from others who studied NK1 receptor mutant mice. For example, Weng et al. (2001) reported that the enhanced responsiveness to repeated electrical stimulation was absent in the NK1 –/– mice, but the responses of spinal neurons to acute noxious mechanical, thermal, and chemical stimuli in NK1 –/– mice were comparable to those in wild-type mice. Suzuki and colleagues (2003) confirmed the absence of wind-up reported by Weng and coworkers (2001) but reported a selective reduction in neuronal responses evoked by a 75-g punctate mechanical stimulus (von Frey) in NK1 –/– mice when they tested a complete range of stimulus intensities. However, responses evoked by brush and lower intensity mechanical stimuli were comparable to those seen in wild-type mice (Suzuki et al. 2003). These investigators also found deficits in thermal stimulus coding at temperatures above 45° C (responses to chemical stimuli were not tested), which is consistent with our results. Although we did not test a quantifiable suprathreshold mechanical stimulus, we observed no deficit in brush-evoked activity in pptA –/– mice. Because SP/NKA are involved in the processing of mechanical stimuli as well (Abbadie et al. 1997; Cao et al. 1998; Mansikka et al. 2000; Mantyh et al. 1997; McCarson and Goldstein 1991), it will be interesting to see whether the properties that we revealed using thermal stimuli will apply for mechanical stimuli.
Recording from muscles, De Felipe et al. (1998) showed that responsiveness to threshold mechanical and electrical stimulation did not differ between wild-type and NK1 –/– mice, but only in the wild-type mice did repeated mechanical or electrical stimulation to the hindpaw increase nociceptive withdrawal reflexes. Thus the intact acute stimulus encoding and the deficits in the cumulative responses to repetitive stimulation, which require afterdischarges, agree with our findings in ppt-A –/– mice. In contrast to our results, Weng et al. (2001) detected no difference in thermal sensitization after mustard oil application, in either wild-type or NK1 –/– mice, but they found impaired sensitization to mechanical stimuli in the knockout mice. The discrepancy between the 2 studies in the development of sensitization to thermal stimuli is likely related to the fact that we tested innocuous temperatures, to which we observed significantly greater sensitization compared with noxious stimuli. By contrast, Weng and colleagues (2001) used only noxious temperatures. In a separate study, Laird and colleagues (2000) found that NK1 –/– mice manifest deficits in visceral pain, but only in response to a prolonged stimulus. Our electrophysiological results in which sustained neuronal activity to prolonged stimuli is lost in the absence of SP/NKA are in good agreement with the deficit in visceral pain in NK1 –/– mice. Taken together, these findings illustrate that it is the duration of the stimulus that distinguishes stimulus encoding properties in NK1 and pptA –/– mice.
The most striking finding in the current study was the profound deficit in the noxious stimulus-induced afterdischarges recorded from WDR neurons, both before and after sensitization was induced. Previous studies suggested that NKA and NK2 receptors contribute more to the enhancement of thermal responses and to sustained neuronal activity than do SP and NK1 receptors (Cumberbatch et al. 1995; Munro et al. 1993). Afterdischarges predominate in WDR neurons and increase in magnitude and duration after persistent injury, either spontaneously (Sotgiu et al. 1995) or in response to thermal stimulation (Palecek et al. 1992). One would predict that increased afterdischarge activity, and resultant temporal summation, would prolong the nociceptive signal, leading to a protracted pain response. Consistent with this hypothesis, rats with nerve injury exhibit prolonged hindpaw elevation after noxious thermal stimulation (Bennett and Xie 1988). In the absence of injury, Dirig and Yaksh (1996) examined the effects of intrathecal administration of SP on thermal hyperalgesia induced by a range of stimulus intensities and found that SP shifts the intensity–response profile in a manner consistent with a multiplicative interaction between SP and stimulus intensity. This gain in spinal somatosensory processing may be achieved through afterdischarge activity, which, based on our results, requires SP/NKA. Although the relationship of these afterdischarges to the behavioral phenotype remains uncertain, in light of our previous work (Cao et al. 1998) in which behavioral withdrawal responses were intact in pptA –/– mice until supranoxious thresholds were reached, we suggest that early and peak responses of WDR neurons to noxious stimuli likely trigger reflex responses; whereas the poststimulus aftersensation (rarely measured behaviorally), particularly to a prolonged noxious stimulus, is dependent on tachykinin transmission. This interpretation is consistent with the finding that NK1 and NK2 antagonists are preferentially effective against prolonged noxious stimuli (Seguin et al. 1995) and with the loss of wind-up in the NK1 –/– mice (De Felipe et al. 1998; Weng et al. 2001).
NK1 receptors are expressed in some deeper laminae of the dorsal horn, but are predominantly found in the superficial laminae of the spinal cord (Brown et al. 1995; Littlewood et al. 1995; Moussaoui et al. 1992; Yashpal et al. 1990). As such, the absence of SP/NKA could affect central nociceptive processing by interactions with NK1-expressing neurons in lamina I (Toda and Hayashi 1993) and/or in the deeper dorsal horn (King et al. 1997b). Targeted cytotoxic lesioning studies have highlighted the importance of lamina I neurons that express NK1 receptors in nociceptive processing. In fact, loss of this subpopulation was sufficient to attenuate responses to noxious stimuli (Mantyh et al. 1997) as well as behavioral hypersensitivity following with injury (Benoliel et al. 1999; Nichols et al. 1999).
Although there is considerable evidence for the modulation of nociceptive-specific neurons in lamina I by SP and/or NKA (Doyle and Hunt 1999; Mantyh et al. 1997; Nichols et al. 1999; Parker et al. 1993; Redburn and Leah 1999), noxious thermal stimuli increase metabolic activity to a greater extent in deep dorsal horn neurons compared with those located more superficially (Coghill et al. 1991). NK1-expressing neurons in deep dorsal horn are of particular interest in their own right because Fos expression (Doyle and Hunt 1999) and NK1 receptor internalization (Abbadie et al. 1997) studies indicate their contribution to spinal nociceptive processing after inflammation. Thus whereas NK1-expressing neurons in the superficial dorsal horn may be essential for enhanced nociceptive processing after injury, it is important to recognize that neurons in the superficial and deep dorsal horn are likely functionally connected (Biella et al. 1997) and therefore are both important contributors to nociceptive processing. To this end, it is worth noting that ablation of NK1-expressing neurons in lamina I prevented central sensitization of neurons located in both the superficial and the deep dorsal horn (Khasabov et al. 2002). Taken together with our results, this finding underscores the influence of SP/NKA, whether direct or indirect, on stimulus intensity coding in WDR neurons in the deep dorsal horn.
Coghill et al. (1993) reported that human subjects use peak sensation to rate pain intensity and that pain ratings to prolonged noxious stimulation are closely correlated temporally to WDR responses recorded in nonhuman primates. Interestingly, only WDR neurons were active during the sensory and affective ("unpleasantness") responses to prolonged pain (Coghill et al. 1993), which suggested that activity of this class of neurons is sufficient to produce pain. We found that neurons from the pptA –/– mice responded only to the peak of the stimulus. Because duration of the noxious stimulus is an important contributor to the relationship between stimulus intensity and pain unpleasantness in humans (Price 2000), our results suggest that SP/NKA prolongation of the discharge of WDR neurons is an important contributor to the unpleasantness response. The lack of influence of SP/NKA on acute stimulus encoding of WDR neurons perhaps explains the failure of NK1 receptor antagonists to provide clinical analgesia in humans (Hill 2000), but suggests that some features of the pain response may be susceptible to block of NK1 receptors.
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ACKNOWLEDGMENTS |
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GRANTS
This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-14627 and NS-21445 and an unrestricted gift from Bristol-Myers Squibb. W. J. Martin was supported by a training grant from the National Institutes of Health.
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. J. Martin, Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065.
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