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Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-1069
Submitted 28 January 2004; accepted in final form 8 March 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Simone et al. 1991; Sluka et al. 1997). Studies in rats also showed that intradermal injection of capsaicin resulted in an increase in background activity, as well as an increase in responses to innocuous and noxious cutaneous stimuli such as brush, press, and pinch of wide dynamic range (WDR) neurons in the spinal dorsal horn (Wu et al. 2001). The sensitization of dorsal horn neurons induced by capsaicin is blocked by antagonists of AMPA, N-methyl-D-aspartate (NMDA), metabotropic glutamate, and NK1 receptors (Dougherty et al. 1992, 1994; Neugebauer et al. 1999, 2000; Palecek et al. 1994; Willis 2001a,b).
Calcitonin gene-related peptide (CGRP) has been implicated in the processing of nociceptive information in the spinal cord (Bennett et al. 2000; Cridland and Henry 1988, 1989; Neugebauer et al. 1996; Oku et al. 1987; Satoh et al. 1992; Sun et al. 2003), where it is found in unmyelinated (C) and thinly myelinated (A
) afferent fibers (Willis and Coggeshall 2004). Capsaicin injection activates C and A primary afferents, resulting in the release of CGRP from the central terminals of primary afferents in the spinal dorsal horn (Carlton et al. 1990; Chung et al. 1988). In behavioral experiments, we found that intradermal injection of capsaicin induced long-lasting mechanical allodynia and hyperalgesia (Sluka and Willis 1997; Sun et al. 2003; Wu et al. 2001). CGRP8-37, a specific antagonist of CGRP1 receptors, prevented or reversed the secondary mechanical hyperalgesia and allodynia induced by capsaicin (Sun et al. 2003).
This study tests the hypothesis that activation of CGRP receptors contributes to the central sensitization of WDR neurons in the spinal cord that is induced by intradermal injection of capsaicin.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Male Sprague-Dawley rats weighing 270-320 g were used in this study. The experiments were approved by the Institutional Animal Care and Use Committee and were consistent with the ethical guidelines of the National Institutes of Health and of the International Association for the Study of Pain. All experimental animals were housed and maintained in accordance with the guidelines of the University of Texas Medical Branch Animal Care and Use Committee.
General preparation and anesthesia
Rats were anesthetized initially with sodium pentobarbital (50 mg/kg, ip) for performing surgery. The trachea was cannulated to provide unobstructed ventilation, and a catheter was inserted into the external jugular vein for maintenance of anesthesia during experiment by continuous infusion of sodium pentobarbital (10 mg/kg/h). The level of anesthesia was frequently checked during the experiment by examining corneal and withdrawal reflexes and observation of the end-tidal CO2 level. Once a stable level of surgical anesthesia was reached, the animals were paralyzed with an initial dose of pancuronium (1 mg/kg), and they were ventilated artificially to maintain an end-tidal CO2 between 3.5 and 4.5%. Paralysis of the musculature was maintained by continuous infusion of pancuronium (0.4-0.6 mg/kg/h). A laminectomy was performed to expose the spinal cord at the T13–L2 vertebral level. The spinal cord was continually bathed in a pool of warm (37°C) mineral oil except for the spinal segments that were to be superfused. Core body temperature was maintained at 37°C by a servo-controlled heating blanket.
Administration of drugs
Capsaicin (Fluka, EC 2069698; 1%, 20 µl) was injected intradermally into the plantar surface of the hindpaw of rats. CGRP8-37 (Sigma) or CGRP (TOCRIS), dissolved in artificial cerebrospinal fluid (ACSF), was applied by controlled superfusion of the spinal cord at the segments from which recordings were made. A specially synthesized silicone rubber was used to form a small well on the cord dorsum at the recording level for controlled superfusion of the spinal cord (Beck et al. 1995). At 30 min after capsaicin injection, the sensitization of WDR cells was tested. To determine the involvement of CGRP in the maintenance of sensitization of WDR cells, CGRP8-37 (1 µM, 15 µl, n = 9) was administered 45 min after capsaicin injection. To assess the role of CGRP receptors in the induction of sensitization, CGRP8-37 (1 µM, 15 µl, n = 9) was administered 5 min before injection of capsaicin. To study the effect of activation of CGRP receptors on the responses of WDR neurons to peripheral mechanical stimuli, CGRP (0.5 µM, 15 µl, n = 6), CGRP8-37 (10 µM, 15 µl, n = 6), CGRP + CGRP8-37 (CGRP, 0.5 µM; CGRP8-37, 5 µM, 15 µl, n = 4), or CGRP + CGRP8-37 (CGRP, 0.5 µM; CGRP8-37, 10 µM, 15 µl, n = 6), was applied by controlled superfusion at the level of recording. In a control group, ACSF was administered instead of CGRP8-37, CGRP, or CGRP + CGRP8-37.
Recording of WDR neurons
Recordings were made from WDR neurons in the dorsal horn. These neurons responded to both innocuous and noxious mechanical stimulation, but best to noxious stimuli. Cells were searched under the small well for controlled superfusion of the spinal cord at the L5 segment using low-impedance (3-5 M
) carbon filament electrodes (Kation Scientific, Minneapolis, MN) and an electronic micromanipulator that advanced in 5-µm steps. Mechanical stimuli were used during the search for dorsal horn neurons (innocuous stimuli consisted of brushing in a stereotyped manner with a camel's hair brush, noxious stimuli were mild pinching with the experimenter's fingers). WDR neurons with receptive fields (RFs) located on the plantar surface of the hindpaw were recorded extracellularly in the L5 segment of the spinal cord. Recordings were made only from single neurons whose spike amplitude could be easily discriminated from spikes of neighboring units. Electrophysiological activity was amplified and displayed on a storage oscilloscope before being sent to a data analysis system (CED 1401, PC) for data collection using spike-2 software that enables computation and storage of peristimulus rate histograms. Throughout the experiment, spike size and configuration were continuously monitored on the digital oscilloscope and with the use of Spike-2 software to confirm that the same WDR neuron was recorded and that the relationship of the recording electrode to the neuron remained constant.
Evoked response measures and experimental design
After the receptive field of the identified WDR neuron was mapped using brush and mild pinch stimuli, graded mechanical stimuli were applied. These consisted of brushing the skin with a camel hair brush in a stereotyped manner (20 strokes/10 s) and sustained applications of two different-sized arterial clips to a fold of skin. One clip produced a sensation of firm pressure (Press, 144 g/mm2) near threshold for pain when applied to human skin, and the other was distinctly painful (Pinch, 583 g/mm2) without causing overt damage to the skin. The background activity was recorded for 5 min before the application of the mechanical stimuli. Each stimulus (Brush, Press, and Pinch) was applied for 10 s followed by a 2-min pause. The capsaicin injection was placed within the receptive field and 1-1.5 cm away from the site for application of the mechanical stimuli. Responses to mechanical stimuli were calculated by subtracting the mean background discharge from the total activity that occurred during the 10-s stimulus.
Statistical analysis
In each group, the baseline activity (background activity and responses to Brush, Press, and Pinch) was regarded as control (100%). The activity of each WDR neuron after drug or ACSF administration was expressed as percent of baseline. Values are presented as means ± SE. For statistical analysis, paired t-test or two-way ANOVA was used, where appropriate, followed by a Student-Newman-Keuls test. In all tests, significance was accepted at the level P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In 64 rats, a total of 64 unidentified WDR neurons with afferent input from the plantar surface of the hindpaw were recorded in segment L5 of the spinal cord at a depth of 260-900 µm from the cord dorsum. Five neurons were located at depths of 260-320 µm, 12 at 320-500 µm, 41 at 500-800 µm, and 6 at 800-900 µm. Most of the neurons in the sample were estimated to be distributed widely in lamina V and VI (500-800 µm). All the recorded neurons exhibited spontaneous activity. The RFs of the neurons in capsaicin experiments were 
1-1.5 cm in diameter. The activity after drugs or ACSF administration is expressed as percent of baseline.
CGRP8-37 reverses the sensitization of WDR neurons induced by intradermal injection of capsaicin
The activity of a representative WDR neuron in the dorsal horn after intradermal injection of capsaicin is shown by rate histograms in Fig. 1A. The top row shows the baseline background activity and responses to brush, press, and pinch stimuli. After the baseline activity was recorded, capsaicin was injected, and 45 min later, ACSF was administered by controlled superfusion of spinal cord. The background activity and responses to brush, press, and pinch stimuli 30 (2nd row), 60 (3rd row), and 90 min (4th row) after capsaicin injection were increased. ACSF had no effect on the increased activity induced by capsaicin (Fig. 1A, 3rd and 4th rows). In another group of neurons, 45 min after intradermal injection of capsaicin, CGRP8-37 was administered by controlled superfusion of the spinal cord. The activity of a representative WDR neuron is shown in Fig. 1B. The background activity and responses to brush, press, and pinch stimuli of WDR neurons were increased 30 min after capsaicin injection (2nd row). However, 15 min after CGRP8-37 application (3rd row), background activity and responses to brush, press and pinch stimuli were reduced compared with 30 min after capsaicin injection (Fig. 1B, 2nd row). This effect of CGRP8-37 was also observed 45 min after CGRP8-37 administration (Fig. 1B, 4th row).
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To test whether CGRP8-37 prevents the sensitization of WDR neurons induced by capsaicin, CGRP8-37 (1 µM) was delivered by controlled superfusion of the spinal cord 5 min before capsaicin injection. In the control group, ACSF was delivered instead of CGRP8-37. Figure 3 shows a typical experiment on one WDR neuron after CGRP8-37 superfusion. At 35 (2nd row) and 65 min (3rd row) after CGRP8-37 administration, the background activity and the responses to brush, press, and pinch mechanical stimuli were not obviously enhanced by capsaicin. The grouped data from a total of nine WDR neurons in each group are presented in Fig. 4. In the ACSF group, there was a significant increase in background activity and responses to brush, press, or pinch stimuli 30 min after capsaicin injection. There was also a significant increase in background activity and response to brush 60 min after capsaicin injection (Fig. 4; ANOVA followed by Student-Newman-Keuls test, P < 0.05). In the CGRP8-37 group, there was no significant change in either background activity or responses to the mechanical stimuli at any time point tested. However, the background activity or responses to mechanical stimuli after capsaicin injection were significantly different between control and CGRP8-37 groups (ANOVA followed by Student-Newman-Keuls test, P < 0.05). The results suggest that preemptive administration of CGRP8-37 prevents the sensitization of WDR neurons induced by capsaicin.
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A total of 28 recorded WDR neurons were divided randomly into five groups. These groups received superfusion of ACSF (n = 6), CGRP (0.5 µM, 15 µl, n = 6), CGRP8-37 (10 µM, 15 µl, n = 6), CGRP + CGRP8-37 (CGRP, 0.5 µM; CGRP8-37, 5 µM, 15 µl, n = 4), or CGRP + CGRP8-37 (CGRP, 0.5 µM; CGRP8-37, 10 µM, 15 µl, n = 6). Figure 5, A and B, shows rate histograms of the activity of representative WDR neurons in the ACSF (control) and the CGRP groups, respectively. There was no difference between the baseline activity (Fig. 5A, top row) and the activity 30 min after ACSF superfusion (2nd row). However, 30 min after superfusion of CGRP, the representative WDR neuron shows an increase in background activity and responses to press and pinch, but not to brush (Fig. 5B, 2nd row) compared with the baseline activity (Fig. 5B, top row). After CGRP superfusion, neurons were considered responsive to CGRP when changes in background activity and responses to mechanical stimuli were increased more than 25% from baseline value. According to this criterion, in three of six WDR neurons tested, there was an increase in background activity after CGRP superfusion. A summary of the grouped data is shown in Fig. 6. At 30 min after superfusion with ACSF (15 µl), there were no significant changes in the activity of naïve WDR neurons (Fig. 6). At 30 min after superfusion of CGRP (0.5 µM, 15 µl), responses to Press and Pinch significantly increased to 156.11 ± 11.45 and 128.19 ± 7.82%, respectively (paired test, P < 0.05), but the responses to brush stimuli were not obviously changed. Because CGRP produced inconsistent effects on background activity of neurons, background activity was slightly, but not significantly increased. Moreover, after washout, the increases in responses induced by CGRP outlasted the CGRP infusion period for at least one-half hour (data not shown). CGRP8-37 (5 µM) inhibited the effects of CGRP, but not completely. CGRP8-37 (10 µM) completely blocked the effect of CGRP. However, there were no significant changes in the activity of WDR neurons after superfusion of CGRP8-37 (10 µM; Fig. 6). These results suggest that administration of CGRP and activation of CGRP receptors induces sensitization of WDR neurons to press and pinch stimuli.
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DISCUSSION |
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, 1992; Simone et al. 1991; Sluka and Willis 1997; Sun et al. 2003; Torebjörk et al. 1992; Wu et al. 2001). Since the nociceptors in the area of secondary hyperalgesia and allodynia are not sensitized after capsaicin injection (Baumann et al. 1991; Lamotte et al. 1992), the development of nociceptive behaviors was attributed to plastic changes and sensitization of neurons in the CNS mainly in the dorsal horn of the spinal cord (reviewed in Willis and Coggeshall 2004). It has been suggested that the sensitization may be due to the actions of neurotransmitters released from the primary afferent fibers on selective receptors in the dorsal horn, chiefly excitatory amino acid and substance P receptors (Dougherty et al. 1992, 1994; Neugebauer et al. 1993, 1994, 1995 1999, 2000; Willis 2001a,b). CGRP, a primary afferent peptide, has also been shown to play an important role in pain perception. However, the involvement of its receptor in dorsal horn neuronal sensitization has not been well established. A previous study (Galeazza et al. 1995) showed that the content of CGRP in the dorsal horn of the spinal cord was decreased in the first 3 days, and then it gradually increased in the 8 days following peripheral tissue inflammation. The amount of pre–pro-CGRP mRNA in dorsal root ganglia was increased at 2 days and remained elevated after 8 days. The increase of pre–pro-CGRP mRNA in dorsal root ganglia preceding the recovery of the content of CGRP in the spinal cord must be responsible for replenishing the peptide in the spinal cord. Another study (Hanesch et al. 1993) demonstrated that CGRP immunoreactivity was up-regulated in dorsal root ganglia following peripheral tissue inflammation. Moreover, this up-regulation was concurrent with the development of inflammatory hyperalgesia. In this study, the role of CGRP receptors in hyperexcitability of dorsal horn neurons following capsaicin injection was investigated. Our findings have shown that application of CGRP8-37, a specific CGRP1 receptor antagonist, prevents and reverses the sensitization of dorsal horn WDR neurons induced by capsaicin. The same dose of CGRP8-37 also retards and reverses secondary mechanical allodynia and hyperalgesia induced by injection of capsaicin in awake behaving rats (Sun et al. 2003). The present electrophysiological results further confirm that activation of CGRP1 receptors in the dorsal horn contributes to the development of central sensitization associated with cutaneous inflammation (Willis 2001a,b).
The effect of local application of CGRP on the activity of WDR neurons was also tested in this study to examine whether selective activation of CGRP receptors can sensitize dorsal horn neurons under normal conditions. When CGRP was administered to the spinal cord, 50% of recorded WDR neurons had an increase in their spontaneous activity, 100% had an increase in responses to press, and 83% to pinch. However, none of the recorded neurons had an increased response to brush. Moreover, the effects of CGRP outlasted the application period of CGRP by 30 min. Our results are in line with previous studies (Biella et al. 1991; Miletic and Tan 1988; Ryu et al. 1988; Yu et al. 2002). On the other hand, administration of CGRP8-37 dose-dependently blocked the CGRP-induced increase in spontaneous activity and the responses of WDR neurons to all the mechanical stimuli used. However, the same dosage of CGRP8-37 (10 µM, 15 µl) had little effect on responses to acute noxious stimuli (press and pinch). This finding is consistent with our behavioral studies showing that CGRP8-37 administration had no significant effect on paw withdrawal threshold to mechanical stimulation of cutaneous tissues in normal rats (Sun et al. 2003). In contrast to our results, CGRP8-37 was shown to reduce the responses of WDR neurons to noxious pressure as well as to innocuous pressure applied to the knee joint of normal rats (Neugebauer et al. 1996) and to increase the latency of the paw withdrawal response and the responses of WDR neurons to peripheral electrical stimuli (Yu et al. 1994, 1999, 2002). These results suggested that the modulation of dorsal horn neuronal responses by CGRP is determined by the type of afferent input. It should be noted here that the concentration of CGRP8-37 used in our experiments (0.15 nmol) was much lower than that used in other experimental studies (3-10 nmol; Yu et al. 1994, 1999); this may be another possible explanation for its weak effect on modulating nociceptive processing. However, the dose we used in this study could successfully antagonize the CGRP (0.5 µM, 15 µl)-induced responses of WDR neurons without affecting the baseline sensory responses. This supports the view that CGRP1 receptors are prominently involved in the transmission or modulation of pathological nociceptive information in the spinal dorsal horn.
Although our findings further support a role for CGRP1 receptors in mediating neural sensitization, the mechanism by which CGRP exerts its action on WDR neurons is not well understood. It has been demonstrated that CGRP can enhance the release of glutamate and aspartate in the spinal cord (Kangra and Randic 1990; Smullin et al. 1990), increase the responses of WDR and nociceptive specific neurons to NMDA or (R,S)-
-amino-3-hydroxy-5-methylisoxazole-4-propionate (Ebersberger et al. 2000), and facilitate the actions of substance P in behavioral and electrophysiological experiments by potentiating the release and inhibiting the degradation of substance P (Biella et al. 1991; LeGreves et al. 1985; Mao et al. 1992; Oku et al. 1987; Schaible et al. 1992; Wiesenfeld-Hallin et al. 1984; Woolf and Wiesenfeld-Hallin 1986). All together, these studies suggest that CGRP may produce its effect on pain transmission and modulation through interaction with substance P and excitatory amino acids. Alternatively, CGRP may be involved in pain transmission independently of substance P and excitatory amino acids. It has been reported that CGRP produces a depolarization by itself (Miletic and Tan 1988; Ryu et al. 1988). However, the long-lasting effect of CGRP after washout suggests that the formation of second messengers is ultimately responsible for the prolonged increase in neuronal excitability. The second messenger systems that are activated by CGRP receptor stimulation and are involved in pain transmission have not been thoroughly investigated. Recent research has shown increased production of cAMP following CGRP stimulation at concentrations of <1 µM in primary cultures of neonatal rat spinal cord (Parsons and Seybold 1997). Moreover, CGRP increases the expression of NK1 receptors by a cAMP-dependent pathway (Seybold et al. 2003). CGRP also phosphorylates ERK by a protein kinase A (PKA)-dependent pathway (Parameswaran et al. 2000), and ERK contributes to the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity (Ji et al. 2002). All the results concerning the signaling pathway downstream of CGRP receptor activation were obtained from in vitro studies. A possible mechanism by which CGRP exerts its effect on dorsal horn neurons is through activation of PKA, a signal transduction mechanism well known to contribute to the sensitization of STT neurons (Sluka et al. 1997; Lin et al. 2002). Interestingly, PKA activated by forskolin induces increased responses of STT to noxious mechanical stimuli, but not to innocuous stimuli (Lin et al. 2002), a change very similar to that produced by activation of CGRP receptors on WDR neurons in our study. Thus this raises the interesting possibility that CGRP may be involved in nociceptive information processing by means of a PKA-dependent pathway. This hypothesis needs to be tested in vivo in the future.
In conclusion, CGRP and CGRP1 receptors play a pivotal role in the development and maintenance of central sensitization. This study provides further evidence to suggest a possible therapeutical target for the treatment of inflammatory pain.
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. D. Willis, Dept. of Neuroscience and Cell Biology, The Univ. of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1069 (E-mail: wdwillis{at}utmb.edu).
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P < 0.05 compared with the value at the same time point in ACSF group.
