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1Departments of Neuroscience and Psychology, Brown University, Providence, Rhode Island; and 2Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana
Submitted 18 April 2005; accepted in final form 18 October 2005
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ABSTRACT |
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INTRODUCTION |
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) and subsequently found to activate the vanilloid TRPV1 receptors (De Petrocellis et al. 2000). More recently, NADA was identified as an endogenous molecule in the mammalian nervous system occurring in several brain nuclei and the dorsal root ganglion (Huang et al. 2002). NADA activates TRPV1 with a potency that is 5 to 10 fold higher than that of any other endovanilloid proposed prior to its discovery (De Petrocellis et al. 2000; Huang et al. 2002; Tóth et al. 2003). Additionally, the affinity of NADA for CB1 receptors is in a similar (high-nanomolar) range to that of the endocannabinoid anandamide (Bisogno et al. 2000; Chu et al. 2003). It seems plausible that NADA may act as a potent endovanilloid and a capable endocannabinoid.
NADA may serve naturally to regulate pain sensitivity. It caused thermal hyperalgesia when administered peripherally (Huang et al. 2002), increased substance P and CGRP release in spinal cord slice, (Huang et al. 2002) and trigeminal cultures (Price et al. 2004), depolarized dorsal root ganglion neurons, and suppressed firing of spinal neurons to mechanical stimuli (Sagar et al. 2004). In addition to influences on nociceptive processing, a range of other physiological effects have been reported. NADA enhanced paired-pulse depression in hippocampal slices (Huang et al. 2002), induced contractile responses in isolated bronchus and urinary bladder (Harrison et al. 2003), caused vasorelaxation (O'Sullivan et al. 2004, 2005), and inhibited activation of NFkB-dependent transcriptional activity in human T cells (Sancho et al. 2004). Most of these effects were capsaicin-like, though some were cannabinoid-like, and still others were suggested to be CB1 and TRPV1 independent. Moreover, it was shown that the potency and the efficacy of NADA could be affected by other factors such as the activity of protein kinase C (Huang et al. 2002; Premkumar et al. 2004). Hence it appears that NADA may participate in a wide array of physiological processes in a rather complex manner. The most salient action of NADA in tests of sensory function is the thermal hyperalgesia observed after peripheral administration, this occurring at sub-microgram doses (Huang et al. 2002). In the present study, we sought to elucidate the neurophysiological basis for this effect. Toward this end, we examined the effects of peripheral administration of NADA on spinal wide dynamic range neurons with the aim of determining the effect of NADA on spontaneous firing and responses to a thermal stimuli ranging from nonnoxious to noxious levels.
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METHODS |
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A total of 61 male Sprague-Dawley rats (300–470 g; Charles River, Boston, MA) were used to conduct the experiments described herein. All protocols were approved by the Brown University Institutional Animal Care and Use Committee.
Drug preparation and administration
NADA was obtained from Cayman Chemicals (Ann Arbor, MI) and BIOMOL International (Plymouth Meeting, PA). 5'-iodoresiniferatoxin (I-RTX) was obtained from Tocris Cookson (Ellisville, MO) and LC Laboratories (Woburn, MA). SR141716A was a gift from Sanofi Richerche (Montpellier, France). All drugs were dissolved in a vehicle of ethanol: emulphor: saline (1:1:18). In the antagonist studies, either I-RTX or SR 141716A was co-administered with NADA in the same solution. Drug(s) or vehicle (50 µl) was injected (intraplantar) in the ipsilateral hindpaw receptive field of the neuron via a 30 gauge needle. Intraplantar doses of NADA (0.5, 1.5, 3, and 5 µg) and the dose of I-RTX (1 µg) employed were based on behavioral assays (Huang et al. 2002). The dose of SR 141716A (10 µg) was based on its affinity for the CB1 receptor (Ki = 2 nM) (Rinaldi-Carmona et al. 1995) and has been demonstrated in previous studies to be sufficient for peripheral CB1 receptor antagonism (Kelly et al. 2003; Richardson et al. 1998).
Electrophysiological methods
Animals were anesthetized with urethan (1.25g/kg ip) and placed in a stereotaxic frame. Body temperature was maintained throughout the course of the experiment via a rectal probe and a heating pad. Laminectomy was performed over the T12–L2 vertebrae to expose the lumbar spinal cord. The spinal cord was stabilized with clamps fastened to the vertebral processes immediately rostral and caudal to the exposed spinal segment. The cord was bathed in warm mineral oil. A tungsten recording electrode (5–6 M
impedance, FHC, Bowdoinham, ME) was lowered to the spinal cord with a micromanipulator (Narashige, Tokyo, Japan). The electrode was advanced slowly into the cord within the depths of 100–1,000 µm from the cord surface with a microdrive (Narashige, Tokyo, Japan) while the experimenter gently tapped the ipsilateral hindpaw to search for spinal neurons with receptive fields in the plantar surface of the paw. Action potentials were recorded extracellularly, digitized, and discriminated by the computer. The size and shape of the action potentials were monitored with the aide of a digital oscilloscope (Tektronix, Beaverton, OR) to ensure that only responses from single cells were recorded. Neurons were classified as wide dynamic range nociceptive neurons if they exhibited increasing firing rates to application of increasing intensity of mechanical stimulation (brush, pressure and pinch) to the hindpaw skin. Cells with high ongoing spontaneous discharges were excluded from the study due to problems associated with statistical analysis of heterogeneous populations.
Assessment of spontaneous firing
On identification of a nociceptive neuron with a receptive field on the plantar surface of the hindpaw, spontaneous firing rates were continuously recorded throughout the experiment. After 
10 min of stable recording of predrug neural activity, NADA (5 µg, 50 µl, i.pl., n = 3) or vehicle (n = 3) was injected in the center of the receptive field, and postdrug firing was recorded without stimulation.
Assessment of heat-evoked firing
The effects of NADA on thermal stimuli were studied in separate groups of animals from those used for the study of the effects on spontaneous activity. Heat-evoked responses were elicited by applying radiant heat to the receptive field on the plantar surface of the paw. A beam of incandescent light was optically focused and directed at the center of the receptive field (skin blackened with a permanent marker to facilitate heat absorption). The intensity of the stimulation was computer controlled by a digital-to-analog converter connected to a voltage controlled DC power supply. The stimulator was adjusted to obtain increasing paw skin temperatures (from 34 to 52°C over 15 s). Data were acquired for 2 s prior to onset of the stimulus, 15 s during ramp-up, and 15 s after stimulus off-set. After characterization of the nociceptive neurons with mechanical brush, pressure, and pinch, their responsiveness to thermal stimulation was assessed. Cells were classified as heat-responsive nociceptive neurons and included in the study if they exhibited increased firing rates in response to increasing temperatures and if the maximal firing rate occurred at a temperature >46°C. After the establishment of stable baseline responses (3 trials at 10-min intervals), NADA (5 µg, n = 9; 3 µg, n = 5; 1.5 µg, n = 7; 0.5 µg, n = 3), vehicle (n = 9), TRPV1 antagonist I-RTX 1 µg + 5 µg NADA (n = 5), CB1 antagonist SR 141716A 10 µg + 5 µg NADA (n = 5), 1 µg I-RTX (n = 4), or 10 µg SR 141716A (n = 4) was injected into the receptive field of the ipsilateral hindpaw. To account for possible changes in the contour of the paw surface from injection, periodic adjustments were made to maintain optimal focus of the light beam at low beam intensity. Postdrug heat-evoked responses were assessed at 10-min intervals for 90 min. Data from the three trials at 20, 30, and 40 min were analyzed as postinjection heat-evoked responses, and the three trials conducted prior to injection as baseline responses. Heat-evoked firing was taken as the response over the 30-s period post stimulus-onset. Injection of 5 µg NADA (n = 4) into the paw contralateral to the recording site was also conducted to assess the possibility of a systemic action of the drug.
Recording site
The location of recording site for each neuron was reconstructed using the atlas of the rat nervous system (Paxinos and Watson 1986) based on the depth of electrode penetration into the cord and the distance of the electrode from the midline.
Statistical analysis
Data were analyzed by repeated-measures ANOVA with BMDP Statistical Software (SPSS, Chicago, IL). The Hyunh-Feldt (1976) correction was applied to interaction terms of repeated measures factors where applicable. The Tukey comparison was employed for post hoc analysis. The Mann-Whitney test was used to analyze data on spontaneous firing (n = 3/group). P < 0.05 was considered statistically significant. For the construction of the log dose-response curve, data points were fitted with a variable slope sigmoidal dose-response curve-fitting algorithm using Hill equation sometimes known as the four-parameter logistic equation (GraphPad Prism4, San Diego, CA)
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RESULTS |
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NADA evokes spontaneous firing in spinal nociceptive neurons
At 10 min after intraplantar injection of 5 µg of NADA (n = 9), increased spontaneous activity of spinal nociceptive neurons was observed compared with injection of vehicle when data from the prestimulus period were analyzed [mean = 10.7 ± 3.5, 3.4 ± 0.8 Hz, respectively; n = 9/group; F(3,48) = 4.00, P < 0.05; Fig. 1A]. The effect dissipated by 20-min postinjection, after which time no significant difference in spontaneous firing was observed. Results from animals in which neural activity was continuously monitored without heat-ramp stimulation revealed that whereas vehicle injections caused a transient increase (<2 min) in firing, injection of NADA caused a sustained increase in spontaneous firing (>10 min). The effect was most prominent in the first 10 min immediately after injection into the hindpaw receptive field with mean firing rates of 17.8 ± 3.0 Hz compared with 5.0 ± 1.0 Hz for vehicle-injected group for most of this period (P < 0.05; n = 3/group; Fig. 1B)
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Peripheral administration of NADA (i.pl., 50 µl) dose-dependently increased the heat-evoked firing in spinal nociceptive neurons with an EC50 of 1.55 µg [R = 0.999; F(4,28) = 2.95, P < 0.05; Fig. 2] at 20–40 µin after injection. Six of nine neurons exhibited a >30% increase in response at the 5 µg dose, 4/5 at 3 µg, 3/7 at 1.5 µg, 0/3 at 0.5 µg, 1/9 at 0 µg. An example neuron illustrating the enhancement of heat-evoked activity by NADA is shown in Fig. 3. This increased firing was not due to a systemic effect of the drug as when NADA was injected in the contralateral paw, the effect was similar to that observed after injection of vehicle in the ipsilateral paw. The mean differences in the overall number of action potentials during a stimulus trial compared with predrug baseline were –26 ± 44 and 25 ± 22 for ipsilateral injection of vehicle and contralateral injection of 5 µg NADA, respectively, versus 355 ± 136 for ipsilateral injection of 5 µg NADA.
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DISCUSSION |
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The findings in this study paralleled our previous observation of behavioral thermal hyperalgesia from peripheral injection of NADA (Huang et al. 2002). The potency of NADA-induced enhancement of neural firing was similar to that for behavioral thermal hyperalgesia (EC50 of 1.55 vs. 1.53 µg, respectively). Moreover, the reversal of NADA-induced enhanced firing of nociceptive neurons by I-RTX agrees with the reversal of NADA-induced thermal hyperalgesia by capsazepine and I-RTX in the behavioral study (Huang et al. 2002). The matching dose dependency and pharmacology suggest that the changes observed in the firing properties of spinal nociceptive neurons underlie the enhanced behavioral nocifensive responses to thermal stimuli.
The data in this study are in agreement with previous studies which reported NADA-evoked increase in intracellular calcium levels in DRG neurons (Huang et al. 2002) and NADA-evoked release of substance P and CGRP in spinal cord slices and trigeminal neuronal culture in a TRPV1-dependent (Huang et al. 2002; Price et al. 2004) and CB1-independent (Price et al. 2004) manner. When taken as a whole, the evidence suggests that NADA, when present in the vicinity of peripheral or spinal sensory neurons, facilitates pain sensitivity predominantly via a TRPV1 mechanism. TRPV1 has been reported to be present on central and peripheral terminals of primary afferent neurons and skin keratinocytes (Denda et al. 2001; Guo et al. 1999; Szallasi et al. 1995; Tominaga et al. 1998). Even though CB1 receptors are also present on peripheral nerves (Hohmann and Herkenham 1999; Sanudo et al. 1999), we did not find NADA-induced hypersensitivity to be mediated by CB1 receptors, evident by the lack of antagonism with SR141716A.
Sagar et al. (2004) found that NADA depolarized and increased intracellular calcium levels in cultured DRG neurons. However, they found that the effects were blocked by both TRPV1 and CB1 antagonists. Sagar et al. (2004) also found that peripheral administration of NADA suppressed firing of spinal neurons to mechanical stimuli and that this suppression was blocked by CB1 antagonist but not TRPV1 antagonist when the stimulus was in the innocuous range and vice versa when the stimulus was in the noxious range of mechanical pressure. It seems that the consequence of NADA on nociceptive neurons may differ depending on the mode of stimulation perhaps leading to thermal hyperalgesia accompanied with mechanical insensitivity, although no behavioral data on the effects of NADA on mechanical stimuli have been reported to date. Alternatively, the population of neurons that were recorded in this study may be different from that reported by Sagar et al. (2004). It is also possible that NADA exerts a complex pattern of effects on nociceptive processing as Bisogno et al. (2000) reported analgesia in mice after systemic administration, and Sancho et al. (2004) recently reported NADA-mediated inhibition of IL-2 and NFkB transcription in T cells, suggesting a role of NADA in immunosuppression and anti-inflammation possibly via a TRPV1- and CB1-independent mechanism.
The stimulus-response functions indicated that the neural responses to thermal stimuli were magnified after peripheral administration of NADA. The increase in spontaneous discharges, which occurred immediately after injection of NADA, may in whole or part establish the delayed sensitized response to thermal stimuli. Enhanced spontaneous and/or evoked activity in spinal neurons is often observed after peripheral application of pro-inflammatory or algesic agents such as Freund's Adjuvant, formalin, carrageenan, and histamine (e.g., Carstens 1997; Dickenson and Sullivan 1987; Menetrey and Basson 1982; Torsney and Fitzgerald 2002). Administration of the TRPV1 antagonist capsaizepine attenuated pain behavior, spinal c-fos expression, and spinal nociceptive responses in carrageenan- and formalin-induced inflammatory pain models (Kelly and Chapman 2002; Kwak et al. 1998; Santos and Calixto 1997). TRPV1-knockout mice exhibit impaired sensitivity to noxious thermal pain and fail to develop thermal hyperalgesia in mustard-oil-induced, Freund's adjuvant-induced, and carrageenan-induced inflammation (Caterina et al. 2000; Davis et al. 2000). Furthermore, PKC isoforms are upregulated and found to be involved in chronic pain (Aley et al. 2000; Martin et al. 1999) and sensitize TRPV1 receptors (Cesare and McNaughton 1996; Cesare et al. 1999; Numazaki et al. 2002; Olah et al. 2002; Premkumar and Ahern 2000; Tominaga et al. 2001; Vellani et al. 2001). Several cellular effects of NADA have been shown to be potentiated by activators of PKC (Huang et al. 2002; Premkumar et al. 2004), and rapid repeated exposure to NADA potentiated cellular responses (Premkumar et al. 2004). Hence our results are consistent with a predominantly pro-inflammatory and -nociceptive role of NADA at peripheral sites and the notion of possible involvement of endogenous NADA acting via TRPV1 in nociceptive neuronal sensitization.
In summary, the present study examined the neurophysiological basis for the thermal hyperalgesic effects of peripherally administered NADA. The increased spontaneous firing and the hypersensitivity of spinal nociceptive neurons and the TRPV1 dependency are consistent with the behavioral thermal hyperalgesia observed in our previous study (Huang et al. 2002). The results suggest a possible pain-sensitizing role of endogenous NADA mediated by TRPV1 in the periphery.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. Walker, Dept. of Psychological and Brain Sciences, Indiana University, 1101 E. 10th St., Bloomington, IN 47405 (E-mail: walkerjm{at}indiana.edu)
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ABSTRACT
INTRODUCTION
) and at 20–40 min after (
) injection of 5 µg NADA in the receptive field in the ipsilateral hindpaw. Bottom left: plot of firing rate by log stimulus intensity (46 to 52°C) demonstrating the systematic encoding of increasing temperatures (R = 0.97) which formed the basis for classifying the neuron as a heat responsive wide-dynamic range neuron. Bottom right: overall firing over the 32 s period for the 3 predrug trials vs.the 3 postdrug trials at 20–40 min.