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1Department of Diagnostic and Biological Sciences, School of Dentistry and 2Departments of Neuroscience and 3Psychiatry, School of Medicine, University of Minnesota, Minneapolis, Minnesota
Submitted 28 April 2006; accepted in final form 10 December 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSGRANTSACKNOWLEDGMENTSREFERENCES |
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; Porreca et al. 2002; Randich et al. 1990). Importantly, it was shown that ascending and descending projections between the spinal cord and brain areas, such as the periaquaductal gray (PAG) and the rostral ventromedial medulla (RVM), form a regulatory loop to control nociceptive transmission in the spinal cord (Suzuki et al. 2002). Further, the descending portion of this regulatory loop that promotes facilitation includes a seotonergic projection that activates 5-HT3 receptors in the spinal cord (Suzuki et al. 2004b). The RVM, consisting of the nucleus raphe magnus and adjacent nuclei, is a major source of descending pathways to the spinal dorsal horn. In addition to well-known inhibitory influences, descending projections from the RVM facilitate responses of spinal nociceptive neurons (Guan et al. 2002; Urban and Gebhart 1999; Urban et al. 1996) and contribute to persistent pain and hyperalgesia (Porreca et al. 2002; Vanderah et al. 2001). Behavioral studies showed that descending facilitation plays a role in inflammatory (Ren and Dubner 1996; Terayama et al. 2002), neuropathic (Pertovaara et al. 1997; Pertovaara and Wei 2003; Suzuki et al. 2004a), and cancer (Donovan-Rodriguez et al. 2006) pain.
Based on their electrophysiological responses to noxious thermal stimulation, RVM neurons have been divided into four classes. The putatively nociceptive-facilitating ON cells produce a burst-like increase in their firing rate in connection with a nociceptive withdrawal reflex. In contrast, OFF cells are thought to inhibit nociceptive transmission as they respond with a temporal pause of their relatively high basal firing rate to noxious peripheral stimulation and are excited by opioids (Fields et al. 1983a,Fields et al. 1983b). Both types of cells play an important role in descending opioid analgesia; ON cells are inhibited whereas OFF cells are (indirectly) excited by opioids (Basbaum and Fields 1984; Fields 2000; Fields et al. 1991). In addition to opioids, a variety of neurotransmitters, modulators and their receptors have been implicated in the control of spinal nociceptive processing descending from the RVM (Julius and Basbaum 2001; Millan 2002). NEUTRAL cells do not exhibit a change in discharge during acute noxious stimulation and their role in descending modulation is unclear. These cells may have a role in persistent pain states as their response properties changed over a course of several hours following inflammation (Miki et al. 2002). Serotonergic neurons represent the fourth class of RVM neurons. Some of these cells are excited or inhibited by noxious heat, whereas the majority behaves as NEUTRAL cells (Gao and Mason 2000). It has been suggested that these cells differ from the classical ON and OFF cells because their discharge evoked by noxious heat is of relatively less magnitude and duration, and they are not affected by opioids (Barbaro et al. 1986; Pan et al. 1993). Although serotonergic cells do not appear to be involved in phasic descending modulation, they may play a role in tonic modulation as related to behavioral or social situations (see (Mason 2001)).
Substance P (SP) (Marson 1989; Marson and Loewy 1985) and neurokinin-1 (NK-1) receptors (Leger et al. 2002; Saffroy et al. 1988; Saffroy et al. 2003) have been identified in the brain stem. In the spinal cord, SP is released from nociceptive afferent fibers following noxious stimulation (Duggan et al. 1987; Schaible et al. 1990), interacts with the NK-1 receptor (Helke et al. 1990), and is involved in modulating excitability of nociceptive neurons (Henry 1976; Radhakrishnan and Henry 1995; Salter and Henry 1991). NK-1 receptor-expressing spinal dorsal horn neurons project to brain stem areas that control spinal excitability via descending pathways (Suzuki et al. 2002; Todd et al. 2000). Loss of spinal neurons that possess the NK-1 receptor prevents the full expression of hyperalgesia produced by inflammation, nerve injury, and capsaicin (Mantyh et al. 1997; Nichols et al. 1999), and prevents central sensitization (Khasabov et al. 2002; Suzuki et al. 2002). It has been shown that the loss of central sensitization following ablation of spinal NK-1 possessing neurons is due, at least in part, to a disruption in descending modulation (Khasabov et al. 2005; Suzuki et al. 2005). Thus SP and NK-1 expressing neurons in the spinal cord play an important role in the development of central sensitization and ensuing hyperalgesia.
Despite the numerous studies of the functions of SP in the spinal cord, little is known about the role of SP and NK-1 receptors in the RVM. Disruption of the gene encoding SP and related tachykinins significantly reduces nociception in mice (Cao et al. 1998). Similarly, ‘knockout’ of the gene that encodes the NK-1 receptor decreases behavioral responses to noxious stimuli and decreases nociceptive transmission in the dorsal horn (Bester et al. 2001; De Felipe et al. 1998; Mogil et al. 2000). Since SP is located in the RVM, and the RVM plays an important role in descending modulation of nociceptive transmission, it is possible that results from these genetic studies are due, in part, to SP and NK-1 expressing neurons in the RVM.
To examine the role of SP and NK-1 expressing neurons in the RVM, we determined the effects of activation or blockade of NK-1 receptors on the excitability of ON and OFF cells in the RVM because of the known contribution of these cells to descending modulation of nociceptive processing. We also examined the distribution of RVM neurons that possess the NK-1 receptor.
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METHODS |
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Male Sprague-Dawley rats (Harlan Industries, Indianapolis, IN) weighing 250-350g were housed and used under approval of the Animal Care Committee at the University of Minnesota. Initial anesthesia was achieved with chloral hydrate (200 mg/kg, ip). A catheter was inserted into an external jugular vein for supplementary anesthetic and the animal was placed in a stereotaxic apparatus. A small craniotomy was made and the dura was removed to allow access of a recording electrode to the medulla. Recordings began 
1 h after surgery. During the experiments, anesthesia was maintained with a continuous intravenous infusion of chloral hydrate. The infusion rate was adjusted so that the rats showed no sign of discomfort, but the tail flick reflex could be evoked by application of noxious heat (51°C for 3–5 s) or mechanical stimuli (pinch) to the tail.
Extracellular recording from RVM neurons
Extracellular, single-unit recordings were made from 51 neurons in the RVM. The mean (±SE) stereotaxic coordinates for all cells were: P = –11.03 ± 0.04 mm (range –10.5 to –11.6 mm) from bregma; L = 0.23 ± 0.03 mm (range: 0.0 to 0.8 mm); and V = 9.92 ± 0.07 mm (range: 9.0 to 10.8 mm) from the cerebellar surface (Paxinos and Watson 1998). Recording/iontophoresis electrodes were constructed from a four- or seven-barreled array of thin wall borosilicate glass capillary tubing (1.5 mm OD, 1.12 m ID, World Precision Instruments, Sarasota, FL). One of the barrels contained a 7-µm carbon fiber creating a low-impedance (0.4–0.8 M
at 1 kHz) recording electrode. Drugs were iontophoretically delivered from the surrounding barrels. Action potentials were displayed on an oscilloscope, and activity of single units was isolated according to their amplitude using a window discriminator. Only neurons whose action potentials were easily discriminated were studied. Collection of neuronal impulses and iontophoretic delivery of drugs were automated with a multifunction instrument control and data acquisition board, PCI-6035E (National Instruments, Austin, TX) interfaced with a computer programmed with LabVIEW. The system recorded and displayed peristimulus time histograms and iontophoresis currents in real time. Action potentials were recorded using an analog to digital conversion at 25 KHz and streamed directly on the hard disk. Recordings were made from ON- and OFF-type neurons (Fields 2000; Fields et al. 1991) that were classed according to their responses evoked by noxious heat or mechanical stimuli (brief pinch) applied to the tail. Only ON and OFF cells that exhibited a clear increase or pause in discharge during noxious stimulation were studied.
Microiontophoresis and drug preparation
Drug barrels of the combined recording/iontophoresis electrode contained one of the following freshly made solutions: 100 mM N-methyl-D-aspartate Na (NMDA) in 100 mM NaCl (pH 8.0), 3 mM [Sar9,Met(O2)11]-substance P (SM-SP) in 100 mM NaCl (pH 6.0), 10 mM L-733,060 HCl in 100 mM NaCl (pH 6.0) and 2% Pontamine Sky Blue in 100 mM sodium acetate. NMDA and Pontamine Sky Blue were delivered by negative currents whereas all other compounds were ejected by positive current. All drugs were obtained from Tocris (Ellisville, MO) except Pontamine Sky Blue, which was purchased from BDH Chemicals (Poole, England). Capsaicin (Sigma, St. Louis, MO) was dissolved in 5% Tween-80 and saline and was injected into the glabrous skin of one randomly selected hindpaw at a dose of 10 µg in 10 µl.
Histological verification of recording sites
Recording sites were marked by ejection of Pontamine Sky Blue with 5 µA negative current for 20min. Although not all marks were found, the depth of recording was noted in all cases so that recording sites could be approximated. At the end of the experiment, animals were killed with an overdose of chloral hydrate and intracardially perfused with physiological saline followed by 10% formalin. Recording sites were verified histologically in 50-µm thin sections counterstained with neutral red. Positions of the Pontamine Sky Blue marks were established with the stereotaxic atlas (Paxinos and Watson 1998). The locations of recording sites in the RVM that were verified histologically are shown in Fig. 1.
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Four rats were deeply anesthetized with sodium pentobarbital (100 mg/kg, ip) and perfused intracardially with 400 ml of 0.1 M PBS followed by 400 ml of 4% paraformaldehyde in 0.1 M PBS. Brain stems were removed, postfixed over night and cryoprotected for 48 h in 30% sucrose. The anatomical boundaries of the RVM was specified as the area of the brain stem reticular formation between inferior olives caudally and trapezoid body rostrally. Serial 50 µm sections of this area were cut on a freezing sliding microtome, collected in PBS, and processed by using a free-floating method. Tissue sections were incubated at room temperature for 1 h in a blocking solution of 10% normal donkey serum in PBS with 0.3% Triton X-100 followed by overnight incubation in mixture of primary antibodies for NMDAR1 subunit of NMDA receptors (mouse anti-NMDAR1, 1:500, Chemicon, Temecula, CA) and NK-1 receptors (guinea pig anti-NK-1 receptor, 1:1000, US Biological, Swampscott, MS). After incubation, sections were washed in PBS three times for 10 min and incubated for 1 h in the mixture of secondary antibodies (donkey anti-mouse conjugated to the fluorescent marker Cy3 1:600, and donkey anti- Guinea pig conjugated to the marker Cy2 1:400 (Jackson ImmunoResearch, West Grove, PA). Sections were again washed in PBS three times for 10 min, mounted on gelatin-coated slides, air dried, dehydrated via an alcohol gradient (50, 70, 80, 95, and 100%), cleared in xylene, and coverslipped with DPX mounted media (Fluka, Buchs Switzerland). To confirm the specificity of immunohistochemical staining, controls included preabsorption with corresponding synthetic peptides or omission of primary antibodies.
Double labeled sections were examined using a Leika confocal microscope and images were captured with a CCD Spot camera for quantification. For quantification, a minimum of 4 nonconsecutive tissue sections were used. Images of NK-1 positive neurons located in RVM were captured confocally (1592 µm2 images with 1 µm plane steps). Only NK-1 positive neurons with visible nuclei were used for quantification. The number of cell bodies immunostained for NMDAR1 subunits and NK-1 receptors were determined in the area of the RVM, and the number of neurons that exhibited double labeling (NK-1 and NMDAR1) were expressed as a percentage of all NMDAR1 positive cells.
Data analysis
Comparisons of the total number of spikes evoked by iontophoretic application of NMDA were made between the various treatment (drug) conditions. Background discharge was recorded for 15 s prior to each application of NMDA, and this value was subtracted from the evoked response which was the discharge for 15 s during and following NMDA. The mean number of impulses evoked by three applications of NMDA was taken as the control (baseline) response. To compare data from different experiments, action potential discharge was normalized to the mean control NMDA-evoked response (100%). Differences in the number of impulses evoked by NMDA for individual cells were assessed by one- or two-way ANOVA, and Student Newman-Keuls tests were used for comparisons between groups. Means (±SE) are given throughout. A P value of <0.05 was considered significant in all cases.
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RESULTS |
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; King et al. 1997; Li and Zhao 1998; Tousignant et al. 1990, Tousignant et al. 1992) and the NK-1 antagonist, L-733,060 (Kramer 2000; Seabrook et al. 1996) were examined. The effects of capsaicin injected into the hindpaw were studied in cells without previous challenge with SM-SP or L-733,060. Lack of effects of capsaicin or SM-SP on OFF cell responses to NMDA
OFF cells exhibited a mean ongoing spontaneous discharge rate of 16.2 ± 7.4 impulses/s (n = 9) which paused during heating of the tail (Figs. 1C and 2A). Spontaneous activity for 5 of the 9 cells also paused in response to innocuous stimulation such as touching the tail or paw (not shown). Responses evoked by iontophoretic application of NMDA (duration of 5 s) were obtained every 2 min using negative ejection currents ranging from 50 to 120 nA. Injection of 10 µg capsaicin into the plantar surface of the hind paw produced a long pause (about a minute) in discharge followed by a gradual return to the basal firing rate (Fig. 2A). Capsaicin did not alter peak firing rates of OFF cells evoked by repeated applications of NMDA. Also, no changes were observed in spontaneous activity following the initial pause in discharge produced by capsaicin, or in NMDA-evoked responses in the presence of iontophoretically applied SM-SP or the NK-1 receptor antagonist, L-733,060 (Fig. 2B and C).
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Capsaicin (10 µg in 10 µl saline) injection into the glabrous skin of the hind paw significantly increased both the spontaneous discharge rate and the iontophoresed NMDA-evoked peak firing rate in 9 of 10 ON cells tested (Fig. 3A). The mean spontaneous activity of all recorded ON cells before any treatment was 2.5 ± 2.6 impulses/s (n = 42) and this increased to 8.1 ± 4.9 (n = 10) impulses/s after the initial burst of activity produced by capsaicin.
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NK-1 receptor activation potentiates ON cell responses to NMDA
Iontophoretic application of the selective NK-1 receptor agonist, SM-SP, produced a significant increase in responses evoked by NMDA in 13 of 17 ON cells (76%). Results were normalized and pooled across experiments and showed that NMDA responses increased to 225.4 ± 63.0% of control values (before SM-SP) (Figs. 5A and 6). Responses to NMDA gradually decreased back to control levels within 10–15 min. Spontaneous activity also increased following SM-SP. Spontaneous discharge rates were 2.5 ± 2.6 impulses/s before application of SM-SP (n = 42) and 8.0 ± 6.2 impulses/s after (n = 13). In 4 of 5 ON cells, the potentiation by SM-SP of the NMDA responses and the increase in spontaneous discharge were completely blocked by iontophoretic application of the NK1 antagonist, L-733,060 (Fig. 5B). Application of L-733,060 alone was examined in 6 neurons and did not alter mean NMDA-evoked responses (Fig. 6).
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Widespread labeling of cells bodies that were immuno-positive for NMDAR1 subunits, an essential subunit of the functionally active NMDA receptor, were found in the RVM in each of the four rats studied. At least 6 non-overlapping 1592 µm2 images (29 images total) have been taken throughout RVM, where NK-1 positive neurons were present. A total of 931 neurons that expressed NMDAR1 immunoreactivity were found (average 32.1 ± 1.5 neurons per examined image). Of these neurons, 75 were immunopositive for NK-1 receptors (2.6 ± 0.2 neurons per image). Nearly all NK-1 positive units also expressed NMDAR1 immunoreactivity (98.6%, or 74 of 75 NK-1 possessing neurons). These data suggest that the majority of neurons in the RVM that are sensitive to SP express NMDA receptors. An example of neurons in the RVM that were immunopositive for SP and NMDAR1 is shown in Fig. 7.
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DISCUSSION |
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Functional properties of excitatory amino acids in the RVM
The role of EAAs located in the RVM has been addressed previously. Microinjection of a relatively high dose of glutamate into the nucleus raphe magnus or nucleus gigantocellularis pars alpha in rats significantly increased tail flick latency (McGowan and Hammond 1993) indicating an analgesic effect. In addition, analgesia evoked by intra-PAG morphine injection was markedly reduced by RVM application of NMDA antagonists in the tail-flick test (Spinella et al. 1996);(van Praag and Frenk 1990).
In contrast, microinjection of a low dose of glutamate into the RVM produced descending facilitation of nociceptive dorsal horn neurons which was similar to that produced by electrical stimulation of the RVM with low current. Higher doses of glutamate produced descending inhibition similar to that produced by electrical stimulation with high current (Zhuo and Gebhart 2002; Zhuo et al. 2002).
In rats with inflamed hind paws, NMDA infusion into the RVM also produced facilitation or inhibition of the tail-flick reflex depending on the dose and time after inflammation, and this effect was antagonized by the NMDA receptor antagonist AP5 (Terayama et al. 2000, Terayama et al. 2002). Both the NMDA and AMPA/kainate classes of glutamate receptors have been implicated in the descending modulation of hyperalgesia. It has been proposed that secondary hyperalgesia involves concurrent activation of descending facilitatory systems and masking of inhibitory systems from the RVM. The descending facilitation involves activation of NMDA receptors in the RVM, whereas the descending inhibition involves activation of nonNMDA receptors in the RVM (Urban et al. 1996). In agreement with this notion, injection into the RVM of NMDA agonists at low doses facilitated, and AMPA receptor agonists inhibited, tail-flick responses during hyperalgesia (Guan et al. 2002). Microinjection of the selective NMDA receptor antagonist, MK-801, into the RVM significantly attenuated the development of mechanical hyperalgesia following nerve injury indicating that NMDA receptors in the RVM are involved in mediating enhanced sensitivity to mechanical stimulation (Wei and Pertovaara 1999). Dynamic plasticity in excitability of RVM neurons has been observed during inflammatory hyperalgesia and is related to changes in NMDA receptor activation (Guan et al. 2002; Terayama et al. 2002). At the molecular level, an up-regulation of mRNAs encoding NMDA subunits in the RVM was detected after inflammation and lasted for several days (Miki et al. 2002). Collectively, these data support a role for NMDA receptors in nociceptive processing within the RVM.
Functional relevance of NK-1 receptors in the RVM
The present study showed that a subset of RVM neurons possesses NK-1 receptors and that nearly all of these also possess NMDA receptors. This finding is in agreement with an earlier report in which NK-1 receptors were identified in the RVM (Proudfit et al. 2003, Proudfit et al. 2005). The aim of our immunohistochemical quantification was to reveal the morphological basis of RVM neuronal responsiveness to NK-1 and NMDA receptor activation. This method of quantification cannot provide information on the proportion between NMDAR1 and NK-1 positive neurons in this area. However, our data suggest that NK-1 positive neurons are a relatively small proportion of all the neurons in the RVM.
In studies using the hot plate test, intracerebroventricular infusion of SP had an antinociceptive or pronociceptive effect depending on the animal's sensitivity to heat, and these effects were antagonized by opioids (Naranjo et al. 1982; Oehme et al. 1980; Stewart et al. 1976). Since SP was administered intracerebroventricularly, the loci mediating the effects of SP are not clear. A number of brain stem nuclei were shown to provide SP-containing projections to the RVM, specifically the raphe magnus. These nuclei include the nucleus reticularis paragigantocellularis, the nucleus cuneiformis, the trigeminal subdivision of the lateral reticularis nucleus, the superior central raphe nucleus and the nucleus pontis oralis and PAG (Beitz 1982). The distribution of NK-1 receptors in relation to ON and OFF cells is unknown. In the present study, we found that activation of NK-1 receptors can increase the excitability of ON cells, but not OFF cells, to NMDA. This suggests that NK-1 receptors may be preferentially located on ON cells and/or terminals presynaptic to these neurons as opposed to OFF cells and their input terminals. It is likely that SP acting on these NK-1 receptors can facilitate EAA transmission either by enhancing their release from presynaptic terminals or by enhancing responses of ON cells to EAAs. Consistent with our findings in vivo, a portion of RVM neurons recorded in brain stem slices were excited by bath application of SP (Hammond et al. 2005). It remains to be determined whether SP can facilitate responses of ON cells to natural stimuli and whether this also occurs through facilitation of EAA transmission.
Although the functional relevance of NK-1 receptors in the RVM needs further investigation, there is emerging evidence that activation of ON cells located in the RVM facilitates nociception. For example, injection of neurotensin or cholecytokinin into the RVM decreased paw withdrawal latency and activated ON cells in a dose-specific manner (Heinricher and Neubert 2004; Neubert et al. 2004) whereas activation of OFF cells produces antinociception (Heinricher et al. 1994; Heinricher and Tortorici 1994; Neubert et al. 2004). Response characteristics of NEUTRAL cells also change over the course of inflammation whereby they can develop response properties similar to ON or OFF cells (Miki et al. 2002). Application of mustard oil to the skin increased the spontaneous activity and reflex-related discharge of ON cells, decreased the spontaneous activity and reflex-related pause in discharge of OFF cells, and decreased the latency of withdrawal from noxious heat (Kincaid et al. 2006). As shown in the present study, intraplantar administration of capsaicin or administration of SP into the RVM produced a similar facilitation of ON cells that was attenuated by an NK-1 receptor antagonist. These results support the notion that an increase in the activity of ON cells is pronociceptive, and that activation of NK-1 receptors in the RVM increases their excitability. Correlative behavioral studies using NK-1 receptor antagonists will provide important information on the functional role of NK-1 receptor activation and sensitization of ON cells in hyperalgesia. The present study suggests that blockade of NK-1 receptors may attenuate capsaicin-evoked hyperalgesia by preventing the sensitization of ON cells. Indeed, preliminary reports indicate that administration of an NK-1 antagonist into the RVM attenuates hyperalgesia following inflammation (LaGraize et al. 2005). However, application of SP to the RVM has been reported to produce thermal hyperalgesia (LaGraize et al. 2006) or antinociception (Proudfit et al. 2003). Thus the precise function of SP in the RVM is unclear and needs further investigation. It is likely that SP is probably not the only modulator of ON cell excitability. For example, it was recently demonstrated that brain-derived neurotrophic factor (BDNF) is released into the RVM following inflammation, and produces hyperalgesia when administered into the RVM (Guo et al. 2006). It will be important to determine the effect of BDNF on response properties of identified RVM neurons.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSGRANTSACKNOWLEDGMENTSREFERENCES |
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GRANTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. A. Simone, Dept. of Diagnostic and Biological Sciences, University of Minnesota, 515 Delaware St. SE, 17-252 Moos Tower, Minneapolis, MN 55455 (E-mail: simon003{at}umn.edu)
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REFERENCES |
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in A, time of heat stimulation and or capsaicin injection. In this and the following figures, 
, time of NMDA application; 
in B and C, time of drug iontophoresis.
, time of capsaicin injection into the hind paw. * and +, significant difference from control; #, a significant difference from the capsaicin only group. Single symbols indicate P < 0.05; double symbols indicate P < 0.01.
