![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Purdue Pharma Discovery Research, Cranbury, New Jersey
Received January 3, 2003; accepted April 3, 2003.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Hayes et al., 2000; McIntyre et al., 2001). In vitro studies have shown that, like the native vanilloid receptor, recombinant VR1 can be activated by a variety of chemical as well as physical stimuli. In vitro, VR1 responds to plant-derived compounds, including capsaicin, a pungent component of chili peppers, lipid mediators such as anandamide (Smart et al., 2000), the lipoxygenase product 12-(S)hydroperoxyeicosatetraenoic acid (Hwang et al., 2000), as well as noxious heat (Caterina et al., 1997) and low pH (Tominaga et al., 1998).
A potential role for VR1 in nociception has been evident for some time because injection of the VR1 agonist capsaicin induces nocifensive and hyperalgesic behaviors in rodents and pain in humans (Szolcsanyi, 1977; Carpenter and Lynn, 1981; Simone et al., 1987, 1989; Gilchrist et al., 1996). Further support for VR1 as a therapeutic target arose from experiments involving capsazepine. Capsazepine is a VR1 antagonist that has been shown to competitively inhibit capsaicin-mediated responses in isolated dorsal root ganglion (DRG) neurons (Bevan et al., 1992a) and tissues from rat (Bevan et al., 1992b; Cholewinski et al., 1993; Maggi et al., 1993; Santicioli et al., 1993; Jerman et al., 2000), mouse (Urban and Dray, 1991), and guinea pig (Ellis and Undem, 1994; Fox et al., 1995; Auberson et al., 2000). In vivo, capsazepine has been shown to inhibit nocifensive and hyperalgesic responses to capsaicin in mice, rats, and guinea pigs (Santos and Calixto, 1997; Walker et al., 2003). However, both in vitro and in vivo studies have indicated that capsazepine also has species-dependent activity. In vitro, capsazepine has been shown to block low pH mediated activation of human or guinea pig, but not rat VR1 (Lou and Lundberg, 1992; Satoh et al., 1993; Fox et al., 1995; McIntyre et al., 2001; Savidge et al., 2002). These in vitro results correlate with the finding that capsazepine reverses inflammatory and neuropathic hyperalgesia in the guinea pig, but not in the rat (Walker et al., 2003).
Together, these data suggest that blockade of low pH induced VR1 activation may be predictive of antihyperalgesic efficacy in vivo. If this hypothesis is valid, then molecules that inhibit pH induced activation of rat VR1, in vitro, would also produce a reduction in hyperalgesia in rat models of chronic pain. In the accompanying report, Valenzano et al. (2003) describe N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) as a potent, selective, and orally bioavailable antagonist of rat VR1. In contrast to capsazepine, BCTC not only blocks the activation of rat VR1 by capsaicin but also by low pH at the native rat VR1 in a skin-nerve preparation. Thus, BCTC has provided us with an opportunity to test our hypothesis that the inhibition of low pH induced activation of VR1 confers in vivo efficacy in models of chronic pain. This report describes the effects of BCTC in models of inflammatory, neuropathic, and capsaicin-induced pain in the rat. The efficacy and side effect profile of BCTC in these models were compared with those of nonsteroidal anti-inflammatory drugs and antiepileptic drugs currently used for the clinical therapy of inflammatory and neuropathic pain, respectively.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
-cyclodextrin (Sigma-Aldrich) by gastric gavage in a dose volume of 10 ml/kg b.wt. Gabapentin (Kemprotec, Middlesborough, UK) was dissolved in saline and administered via i.p. injection in a dose volume of 2 ml/kg. Capsaicin (Sigma-Aldrich) was used in all experiments as its free base. The procedure of Gilchrist et al. (1996) was used to dissolve the capsaicin. Briefly, 6 mg of capsaicin was first dissolved in 0.14 ml of polyoxyethylene (20) sorbitan mono-oleate (Tween 80) by gently heating the solution to approximately 70°C. The solution was then diluted with 1.86 ml of 0.9% sodium chloride using an ultrasonic bath, and passed through a 0.20-µm filter. The final concentration of the capsaicin solution was 3 µg/µl. Intraplantar injections of the capsaicin solution were given in a 10-µl volume using a 100-µl Hamilton syringe fitted with a 27-gauge needle. The Tween 80/saline vehicle was used for control injections. Animals. The Purdue Institutional Animal Care and Use Committee approved all animal procedures according to the guidelines of the Office of Laboratory Animal Welfare. Male Sprague-Dawley rats (Taconic Farms, Germantown, NY), weighing 180 to 200 g at the start of acute and inflammatory experiments or 90 to 110 g at the start of nerve ligation experiments, were used. Animals were group-housed and had free access to food and water at all times, except before oral administration of drugs when food was removed for 16 h before dosing. For comparison with compound-treated groups, animals treated with the appropriate drug vehicle were included in each experiment. The volume of administration was identical for vehicle- and compound-treated rats, and rats were identical with respect to all other experimental procedures.
Capsaicin-Induced Hyperalgesia. Intraplantar injection of capsaicin (30 µg) was used to induce mechanical and thermal hyperalgesia, as described previously (Gilchrist et al., 1996). The paw pressure assay was used to assess capsaicin-induced mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWTs) to a noxious mechanical stimulus were determined using an analgesymeter (model 7200; Ugo Basile, Varese, Italy) (Walker et al., 2001). Cut-off was set at 250 g and the endpoint was taken as complete paw withdrawal. PWTs were determined once for each rat at each time point. All rats were tested for baseline PWT and 1 h later, animals received a single dose of 1, 3, 10, or 30 mg/kg BCTC or vehicle (p.o., volume = 10 ml/kg, n = 10/group). Thirty minutes later, under isofluorane/oxygen anesthesia, rats received a single intraplantar injection of 30 µg of capsaicin or vehicle in a 10-µl volume. Ninety minutes after the intraplantar injection of capsaicin, PWTs were determined again.
The plantar test was used to assess capsaicin-induced thermal hyperalgesia (n = 8/group). For this test, hind paw withdrawal latencies (PWLs) to a noxious thermal stimulus were determined using the technique described by Hargreaves et al. (1988) using a plantar test apparatus (model 7370-371; Ugo Basile). Cut-off was set at 32 s, and any directed paw withdrawal from the heat source was taken as the endpoint. To assess the effects of BCTC on the development of capsaicin-induced thermal hyperalgesia rats were treated as described above for capsaicin-induced mechanical hyperalgesia, but PWLs were measured 30 min after capsaicin injection.
Inflammatory Hyperalgesia. The efficacy of BCTC against hyperalgesia associated with inflammation was investigated using the Freund's complete adjuvant (FCA) model (Walker et al., 2001). Mechanical and thermal hyperalgesia were measured in separate groups of rats (n = 8–20/group), according to the procedure described above. Baseline PWTs or PWLs were determined, and rats were then anesthetized with isofluorane/oxygen and received an intraplantar injection of 100% FCA (50 µl). Twenty-four hours after FCA treatment, predrug PWT or PWL measurements were taken and then rats received a single dose of 1, 3, 10, or 30 mg/kg BCTC, 30 mg/kg indomethacin, or vehicle (p.o., volume = 10 ml/kg). PWTs or PWLs were determined again 2, 4, 6, and 24 h postdrug administration.
Hyperalgesia and Allodynia after Nerve Injury. The partial sciatic nerve ligation model was used as a model of nerve injury-related pain in rats, as described previously by Seltzer et al. (1990). Partial ligation of the left sciatic nerve was performed under isoflurane/O2 inhalation anesthesia. After induction of anesthesia, the left thigh was shaved and cleaned. The sciatic nerve was exposed at high thigh level through a small incision and was carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off the common sciatic nerve. A 7-0 silk suture was inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle, and tightly ligated so that the dorsal one-third to one-half of the nerve thickness was held within the ligature and the wound was closed in two layers. Sham-operated control rats underwent an identical dissection on the left hind limb, but the sciatic nerve was not dissected away from the surrounding muscle nor ligated. After surgery, animals were weighed and placed on a warm pad until they recovered from anesthesia.
The effects of BCTC on mechanical hyperalgesia and tactile allodynia were measured 14 to 17 days postsurgery (n = 8–10/group). Mechanical hyperalgesia was assessed using the paw pressure technique before, 2, 4, 6, and 24 h after drug administration. To assess tactile allodynia, rats (n = 10/group) were placed in clear Plexiglas compartments with a wire mesh floor and were allowed to habituate for a period of at least 15 min. After habituation, a series of von Frey monofilaments were presented to the plantar surface of the left (operated) foot of each rat. The series consisted of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials were conducted with each filament, with each trial separated by approximately 2 min. Each presentation lasted for a period of 4 to 8 s, or until a nocifensive withdrawal behavior was observed. Flinching, paw withdrawal, or licking of the paw were all considered nocifensive behavioral responses. Tactile allodynia was assessed before and 2 h postdrug administration.
Ataxia/Motor Coordination. To examine the potential effects of BCTC on motor performance, rats were tested using the rotarod assay. The rotarod speed was maintained at 30 rpm, with the maximum time spent on the rotarod set at 300 s. Rats (n = 8–10/group) received two training trials on the first day, were fasted overnight, and then received a single dose of either 10, 30, or 50 mg/kg BCTC, or 100 mg/kg gabapentin (i.p.) as a positive control. Rats were tested on the rotarod 2 and 4 h after drug administration.
Statistical Analysis. For studies involving mechanical or thermal hyperalgesia, tail-flick, or rotarod latencies, untransformed data were analyzed using a one-way analysis of variance. In instances where a significant main effect was detected, planned comparisons were made using Fisher's PLSD test. The level of significance was set at p < 0.05. For studies involving tactile allodynia, analyses were performed using an analysis of covariance model for each time, with log value of the median fiber weight (FW50) required to evoke a nocifensive response at hour 0 (baseline) as the covariate. A t test for each pair wise comparison based on this model was performed, using PROC GLM of SAS (version 6.12).
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
As reported previously (Gilchrist et al., 1996) intraplantar injection of capsaicin (30 µg) also induced mechanical hyperalgesia that lasted longer than the coincident thermal hyperalgesia. Our preliminary experiments indicated that maximal decreases in PWT occurred 90 min postcapsaicin injection (data not shown). There was a significant main effect of treatment on PWT, indicating a dose-dependent reversal of capsaicin-induced mechanical hyperalgesia by BCTC [F(5,41) = 4.008; p < 0.01]. Pretreatment with BCTC (30 mg/kg) 30 min before capsaicin injection significantly inhibited capsaicin-induced mechanical hyperalgesia relative to rats treated with capsaicin alone (p < 0.05; Fig. 1).
|
BCTC Reduces Thermal and Mechanical Hyperalgesia Associated with Inflammation. Intraplantar injection of 50 µl of FCA resulted in the development of thermal hyperalgesia as indicated by decreased PWL to a noxious thermal stimulus (Fig. 2). Oral administration of BCTC produced a dose-dependent reduction in thermal hyperalgesia 2 [F(5,42) = 8.892; p < 0.001] and 4 h postadministration [F(5,42) = 6.306; p < 0.001]. BCTC (3 and 10 mg/kg p.o.) produced significant antihyperalgesia 2 h after administration (p < 0.05). These effects were comparable both in terms of efficacy and duration of action to the nonsteroidal anti-inflammatory drug indomethacin (30 mg/kg p.o; p < 0.05; Fig. 2). The effects of BCTC were restricted to the hyperalgesia associated with inflammation or injury and do not reflect an acute analgesic activity because PWTs from the noninjured hind paw were not affected by systemic BCTC administration (data not shown).
|
Intraplantar injection of 50 µl of FCA also resulted in the development of mechanical hyperalgesia, determined using the paw pressure assay (Fig. 3). BCTC (1–30 mg/kg p.o.) produced a dose-dependent reversal of FCA-induced mechanical hyperalgesia at 2, 4, and 6 h postadministration (p < 0.001 at each time point). BCTC significantly reduced FCA-induced mechanical hyperalgesia after oral administration at doses as low as 3 mg/kg (4 h) and at higher doses (10 and 30 mg/kg p.o.) were effective for up to 6 h (Fig. 3). The effects of BCTC were similar to indomethacin (30 mg/kg p.o.) in terms of efficacy, but indomethacin was only effective at 2 and 4 h after administration.
|
BCTC Reduces Mechanical Hyperalgesia Associated with Nerve Injury. Partial ligation of the sciatic nerve resulted in the development of mechanical hyperalgesia within 2 weeks of surgery. Administration of BCTC to rats 14 to 18 days after partial ligation of the sciatic nerve resulted in a significant and dose-dependent reversal of this mechanical hyperalgesia [F(6,89) = 10.675; p < 0.001; Fig. 4]. Oral administration of BCTC (1–30 mg/kg) produced a significant reversal of mechanical hyperalgesia in the partially denervated rat hind paw for at least 6 h after administration (p < 0.01). The effects of administration of BCTC (10 mg/kg p.o.) were similar to those seen after administration of gabapentin (100 mg/kg i.p,), but with a longer duration of action (6 versus 4 h; Fig. 4).
|
BCTC Reduces Tactile Allodynia Associated with Nerve Injury. Partial ligation of the sciatic nerve also resulted in the development of tactile allodynia that was evident within 14 days of surgery (Fig. 5A). Administration of 10 mg/kg BCTC to rats 14 to 18 days after partial ligation of the sciatic nerve resulted in the development of tactile allodynia as determined by a significant decrease in the median fiber weight, or the fiber weight required to evoke a hindpaw withdrawal with a 50% frequency relative to vehicle-treated controls. Administration of 10 mg/kg BCTC significantly increased the log FW50 at 2 h postadministration (p < 0.01; Fig. 5B). Administration of 100 mg/kg gabapentin (i.p.) also significantly increased the log FW50 in nerve-injured rats 2 h postadministration (p < 0.01; Fig. 5B).
|
Side Effect Profiling: Ataxia. A common side effect of compounds used to treat neuropathic pain is ataxia, which can confound the interpretation of behavioral assays. A role for VR1 in motor function has not been described; however, we tested rats for motor function using the rotarod assay. BCTC did not affect rotarod performance at 2 or 4 h after administration at doses up to 50 mg/kg, whereas gabapentin (100 mg/kg i.p.) produced in a significant decrease in rotarod performance 2 h postadministration (p < 0.05; Fig. 6).
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The VR1 antagonist capsazepine has also been used in many studies to investigate the role of VR1 in acute and chronic nociception. However, recent studies have revealed species-specific pharmacological actions of capsazepine that may limit its applicability in some animal models (Lou and Lundberg, 1992; Satoh et al., 1993; Fox et al., 1995; McIntyre et al., 2001; Savidge et al., 2002; Walker et al., 2003). Although capsazepine can inhibit activation of rat VR1 by capsaicin, Valenzano et al. (2003) found it to be ineffective at blocking acid-mediated VR1 currents, and is similarly ineffective at reversing pain behaviors associated with inflammation in rats (Walker et al., 2003). However, the pharmacological profile of capsazepine is markedly different in guinea pigs compared with rats. Capsazepine is effective at inhibiting both the acid- and capsaicin-induced VR1 currents at guinea pig VR1 (Savidge et al., 2002) and has been shown to reduce inflammatory and nerve injury-related pain in guinea pigs (Walker et al., 2003). Thus, the species-dependent activity of capsazepine to inhibit low pH induced currents at VR1 correlates with its ability to reduce hyperalgesia in models of chronic pain.
In contrast to capsazepine, BCTC inhibits the activation of rat VR1 by either capsaicin or low pH (Valenzano et al., 2003). The unique pharmacological profile of BCTC at the rat VR1 provided us with an opportunity to test the hypothesis that the effects of VR1 blockers in chronic pain models may be predicted by their ability to inhibit low pH induced activation of VR1. We found that pretreatment with BCTC effectively inhibits the VR1 agonist effects of capsaicin in the rat in vivo (Fig. 1). These results were consistent with the findings of Valenzano et al. (2003) who demonstrated using an ex vivo rat skin-nerve preparation that BCTC completely inhibited the activation of nociceptors by capsaicin.
However, the most striking findings of this study were those indicating that BCTC is effective in reversing established thermal and mechanical hyperalgesia associated with inflammation (Figs. 2 and 3) or nerve injury (Figs. 4 and 5). The effects of BCTC were restricted to the hyperalgesia associated with inflammation or injury and do not reflect an acute analgesic activity because PWTs from the noninjured hind paw were not affected by systemic BCTC administration (data not shown). Likewise, BCTC did not produce any impairment of locomotor activity over and above the dose range that produced antihyperalgesic effects (Fig. 6). These findings are interesting in light of the recent study by Walker et al. (2002) indicating that systemic administration of the VR1 antagonist capsazepine effectively reverses mechanical hyperalgesia associated with inflammation or nerve injury in the guinea pig but was ineffective in rat models of chronic pain. These differences reflect the different molecular pharmacological profiles of capsazepine versus BCTC at rat VR1, in vitro. Valenzano et al. (2003) have demonstrated that unlike capsazepine, BCTC potently antagonizes low pH induced activation of recombinant or native rat VR1. This suggests that the in vivo efficacy of VR1 antagonists in models of chronic pain may be predicted by their ability to inhibit pH induced activation of VR1. Because both capsazepine and BCTC antagonize capsaicin-induced activation of VR1, in vitro and in vivo, this action seems to be less predictive of a VR1 antagonist's efficacy in chronic pain states.
We have found that the VR1 antagonist BCTC (3–30 mg/kg p.o.) effectively reverses both thermal and mechanical hyperalgesia associated with inflammation in the rat (Figs. 2 and 3). However, whereas Walker et al. (2003) reported that capsazepine was weakly active against thermal hyperalgesia associated with inflammation in the guinea pig, we found that VR1 blockade via BCTC provided effective reversal of inflammatory hyperalgesia in the rat. Although this may indicate further differences in the molecular pharmacology of BCTC versus capsazepine at VR1, we cannot rule out the possibility that different behavioral phenotypes make the measurement of thermal hyperalgesia more robust in the rat as opposed to the guinea pig. Regardless the explanation, we know that the hyperalgesic effects of heat cannot be explained by the action of VR1 alone, because mice lacking VR1 retain the sensation of noxious heat (Caterina et al., 2000; Davis et al., 2000) and two VR1 homologs, VRL-1 (TRPV2) and TRPV3, have been reported to be insensitive to capsaicin or protons but respond to either high or low threshold heat stimulation (Caterina et al., 1999; Peier et al., 2002).
We have found that BCTC effectively reversed hypersensitivity to mechanical stimuli after inflammation or nerve injury. Stimuli that activate VR1 have been shown to induce mechanical hypersensitivity. To this end, intraplantar injection of either capsaicin (Simone et al., 1987, 1989; Gilchrist et al., 1996) or hyaluronic acid (Hamamoto et al., 1998) results in the development of mechanical hyperalgesia. In fact, the mechanical hyperalgesia observed after capsaicin injection is more robust than the thermal hyperalgesia both in terms of duration of action and the size of the area of secondary hyperalgesia (Gilchrist et al., 1996). There is also evidence that the mechanisms underlying the thermal and mechanical hyperalgesia after capsaicin injection differ. Thermal hyperalgesia is thought to be due to sensitization of nociceptors because it is restricted to the immediate area of injection, whereas central mechanisms may underlie the mechanical hyperalgesia because the sensitivity is seen in a larger area surrounding the site of injection (Simone et al., 1987, 1989; LaMotte et al., 1991). It has been shown that intradermal capsaicin injection facilitates the responses of dorsal horn neurons due to input of low threshold mechanoreceptors and nociceptors (LaMotte et al., 1991; Simone et al., 1991). In inflamed tissue, local pH decreases may ultimately activate VR1, sensitizing nociceptors and low threshold mechanoreceptors, decreasing the threshold at which mechanical stimuli result in the detection of noxious stimuli.
The ability of BCTC to reduce tactile allodynia and mechanical hyperalgesia after partial ligation of the sciatic nerve may be attributed, in part, to altered expression of VR1 in this nerve injury model. Hudson et al. (2001) recently demonstrated that partial ligation of the sciatic nerve results in decreased VR1 immunoreactivity in damaged (ligated) neurons, but increased VR1 immunoreactivity in undamaged neurons. In another rat model of neuropathy, tight ligation of the L5 spinal nerve resulted in a significant decrease of VR1-immunoreactivity in the injured L5 DRG neurons, with a concomitant increase in VR1-immunoreactivity in the uninjured L4 DRG neurons. Interestingly, the increased VR1-immunoreactivity was present not only in C-fibers, but also in myelinated A-fibers, as well, which could also explain the ability of BCTC to block mechanical sensitivity after nerve injury (Hudson et al., 2002). The increased levels of VR1 may then also prime the sensory neurons to respond to other physiological consequences of nerve damage that occur post injury, such as the release of inflammatory mediators from macrophages during Wallerian degeneration (Tracey and Walker, 1995).
The findings reported here provide strong support for a role for VR1 in the pathology of chronic pain, both of inflammatory and neuropathic origin. Moreover, the in vitro characterization of BCTC (Valenzano et al., 2003) indicates that the ability of VR1 antagonists to block low pH induced channel opening may be a key component in predicting the in vivo efficacy of VR1 antagonists in models of chronic pain.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
ABBREVIATIONS: VR1, vanilloid receptor 1; DRG, dorsal root ganglion; BCTC, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide; PWT, paw withdrawal threshold; PWL, paw withdrawal latency; FCA, Freund's complete adjuvant; PLSD, protected least significant difference; FW50, median fiber weight.
Address correspondence to: Kenneth J. Valenzano, 6 Cedarbrook Dr., Cranbury, NJ 08512. E-mail: ken.valenzano{at}pharma.com
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Auberson S, Lacroix JS, and Lundberg JM (2000) Modulation of capsaicin-sensitive nerve activation by low pH solutions in guinea-pig lung. Pharmacol Toxicol 86: 16–23.[CrossRef]
Bevan S, Hothi S, Hughes G, James IF, Rang HP, Shah K, Walpole CS, and Yeats JC (1992a) Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol 107: 544–552.[Medline]
Bevan S, Rang H, and Shah K (1992b) Capsazepine does not block the proton-induced activation of rat sensory neurones. Br J Pharmacol 107: 235P.
Carpenter SE and Lynn B (1981) Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin. Br J Pharmacol 73: 755–758.[Medline]
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, and Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science (Wash DC) 288: 306–313.
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, and Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature (Lond) 398: 436–441.[CrossRef][Medline]
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, and Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature (Lond) 389: 816–824.[CrossRef][Medline]
Cholewinski A, Burgess GM, and Bevan S (1993) The role of calcium in capsaicininduced desensitization in rat cultured dorsal root ganglion neurons. Neuroscience 55: 1015–1023.[CrossRef][Medline]
Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, et al. (2000) Vanilloid receptor 1 is essential for inflammatory thermal hyperalgesia. Nature (Lond) 405: 183–187.[CrossRef][Medline]
Ellis JL and Undem BJ (1994) Inhibition by capsazepine of resiniferatoxin- and capsaicin-induced contractions of guinea pig trachea. J Pharmacol Exp Ther 268: 85–89.
Fox AJ, Urban L, Barnes PJ, and Dray A (1995) Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig. Neuroscience 67: 741–752.[CrossRef][Medline]
Gilchrist HD, Allard BL, and Simone DA (1996) Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats. Pain 67: 179–188.[CrossRef][Medline]
Hamamoto DT, Ortiz-Gonzalez XR, Honda JM, and Kajander KC (1998) Intraplantar injection of hyaluronic acid at low pH into the rat hindpaw produces tissue acidosis and enhances withdrawal responses to mechanical stimuli. Pain 74: 225–234.[CrossRef][Medline]
Hargreaves K, Dubner R, Brown F, Flores C, and Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32: 77–88.[CrossRef][Medline]
Hayes P, Meadows HJ, Gunthorpe MJ, Harries MH, Duckworth DM, Cairns W, Harrison DC, Clarke CE, Ellington K, Prinjha RK, et al. (2000) Cloning and functional expression of a human orthologue of rat vanilloid receptor-1. Pain 88: 205–215.[CrossRef][Medline]
Hudson LJ, Bevan S, McNair K, Gentry C, Fox A, Kuhn R, and Winter J (2002) Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia. J Neurosci 22: 2660–2668.
Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, and Winter J (2001) VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 13: 2105–2114.[CrossRef][Medline]
Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, and Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97: 6155–6160.
Jerman JC, Brough SJ, Prinjha R, Harries MH, Davis JB, and Smart D (2000) Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology. Br J Pharmacol 130: 916–922.[CrossRef][Medline]
LaMotte RH, Shain CN, Simone DA, and Tsai EF (1991) Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 66: 190–211.
Lou YP and Lundberg JM (1992) Inhibition of low pH evoked activation of airway sensory nerves by capsazepine, a novel capsaicin-receptor antagonist. Biochem Biophys Res Commun 189: 537–544.[CrossRef][Medline]
Maggi CA, Bevan S, Walpole CS, Rang HP, and Giuliani S (1993) A comparison of capsazepine and ruthenium red as capsaicin antagonists in the rat isolated urinary bladder and vas deferens. Br J Pharmacol 108: 801–805.[Medline]
McIntyre P, McLatchie LM, Chambers A, Phillips E, Clarke M, Savidge J, Toms C, Peacock M, Shah K, Winter J, et al. (2001) Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 132: 1084–1094.[CrossRef][Medline]
Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, et al. (2002) A heat-sensitive TRP channel expressed in keratinocytes. Science (Wash DC) 296: 2046–2049.
Santicioli P, Del Bianco E, Figini M, Bevan S, and Maggi CA (1993) Effect of capsazepine on the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) induced by low pH, capsaicin and potassium in rat soleus muscle. Br J Pharmacol 110: 609–612.[Medline]
Santos AR and Calixto JB (1997) Ruthenium red and capsazepine antinociceptive effect in formalin and capsaicin models of pain in mice. Neurosci Lett 235: 73–76.[CrossRef][Medline]
Satoh H, Lou YP, and Lundberg JM (1993) Inhibitory effects of capsazepine and SR 48968 on citric acid-induced bronchoconstriction in guinea-pigs. Eur J Pharmacol 236: 367–372.[CrossRef][Medline]
Savidge J, Davis C, Shah K, Colley S, Phillips E, Ranasinghe S, Winter J, Kotsonis P, Rang H, and McIntyre P (2002) Cloning and functional characterization of the guinea-pig vanilloid receptor 1. Neuropharmacology 43: 450–456.[CrossRef][Medline]
Seltzer Z, Dubner R, and Shir Y (1990) A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43: 205–218.[CrossRef][Medline]
Simone DA, Baumann TK, and LaMotte RH (1989) Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38: 99–107.[CrossRef][Medline]
Simone DA, Ngeow JY, Putterman GJ, and LaMotte RH (1987) Hyperalgesia to heat after intradermal injection of capsaicin. Brain Res 418: 201–203.[CrossRef][Medline]
Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, and Willis WD (1991) Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 66: 228–246.
Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, and Davis JB (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129: 227–230.[CrossRef][Medline]
Szolcsanyi J (1977) A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain. J Physiol (Lond) 73: 251–259.
Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, and Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21: 531–543.[CrossRef][Medline]
Tracey DJ and Walker JS (1995) Pain due to nerve damage: are inflammatory mediators involved? Inflamm Res 44: 407–411.[CrossRef][Medline]
Urban L and Dray A (1991) Capsazepine, a novel capsaicin antagonist, selectively antagonises the effects of capsaicin in the mouse spinal cord in vitro. Neurosci Lett 134: 9–11.[CrossRef][Medline]
Valenzano KJ, Grant ER, Wu G, Hachicha M, Schmid L, Tafesse L, Sun Q, Rotshteyn Y, Francis J, Limberis J, et al. (2003) N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide) (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: 1. In vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther 306: 377–386.
Walker K, Bowes M, Panesar M, Davis A, Gentry C, Kesingland A, Gasparini F, Spooren W, Stoehr N, Pagano A, et al. (2001) Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain. Neuropharmacology 40: 1–9.[Medline]
Walker K, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, and McIntyre P (2003) The VR1 antagonist, capsazepine, reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 304: 56–62.
This article has been cited by other articles:
|
|
 |
|
  J. Vriens, G. Appendino, and B. Nilius Pharmacology of Vanilloid Transient Receptor Potential Cation Channels Mol. Pharmacol., June 1, 2009; 75(6): 1262 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohta, T. Imagawa, and S. Ito Involvement of Transient Receptor Potential Vanilloid Subtype 1 in Analgesic Action of Methylsalicylate Mol. Pharmacol., February 1, 2009; 75(2): 307 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. McGaraughty, K. L. Chu, B. S. Brown, C. Z. Zhu, C. Zhong, S. K. Joshi, P. Honore, C. R. Faltynek, and M. F. Jarvis Contributions of Central and Peripheral TRPV1 Receptors to Mechanically Evoked and Spontaneous Firing of Spinal Neurons in Inflamed Rats J Neurophysiol, December 1, 2008; 100(6): 3158 - 3166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Escalera, C. A. von Hehn, B. F. Bessac, M. Sivula, and S.-E. Jordt TRPA1 Mediates the Noxious Effects of Natural Sesquiterpene Deterrents J. Biol. Chem., August 29, 2008; 283(35): 24136 - 24144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Vetter, W. Cheng, M. Peiris, B. D. Wyse, S. J. Roberts-Thomson, J. Zheng, G. R. Monteith, and P. J. Cabot Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization J. Biol. Chem., July 11, 2008; 283(28): 19540 - 19550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Lehto, R. Tamir, H. Deng, L. Klionsky, R. Kuang, A. Le, D. Lee, J.-C. Louis, E. Magal, B. H. Manning, et al. Antihyperalgesic Effects of (R,E)-N-(2-Hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a Novel Transient Receptor Potential Vanilloid Type 1 Modulator That Does Not Cause Hyperthermia in Rats J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 218 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohta, T. Imagawa, and S. Ito Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1): TONIC INHIBITORY REGULATION OF EXTRACELLULAR SODIUM THROUGH THE EXTERNAL PROTONATION SITES ON TRPV1 J. Biol. Chem., April 4, 2008; 283(14): 9377 - 9387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. U. De Schepper, J. G. De Man, N. E. Ruyssers, A. Deiteren, L. Van Nassauw, J.-P. Timmermans, W. Martinet, A. G. Herman, P. A. Pelckmans, and B. Y. De Winter TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats Am J Physiol Gastrointest Liver Physiol, January 1, 2008; 294(1): G245 - G253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Gavva, A. W. Bannon, D. N. Hovland Jr., S. G. Lehto, L. Klionsky, S. Surapaneni, D. C. Immke, C. Henley, L. Arik, A. Bak, et al. Repeated Administration of Vanilloid Receptor TRPV1 Antagonists Attenuates Hyperthermia Elicited by TRPV1 Blockade J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 128 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Gunthorpe, S. L. Hannan, D. Smart, J. C. Jerman, S. Arpino, G. D. Smith, S. Brough, J. Wright, J. Egerton, S. C. Lappin, et al. Characterization of SB-705498, a Potent and Selective Vanilloid Receptor-1 (VR1/TRPV1) Antagonist That Inhibits the Capsaicin-, Acid-, and Heat-Mediated Activation of the Receptor J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1183 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tang, Y. Chen, Z. Chen, P. M. Blumberg, A. P. Kozikowski, and Z. J. Wang Antinociceptive Pharmacology of N-(4-Chlorobenzyl)-N'-(4-hydroxy-3-iodo-5-methoxybenzyl) Thiourea, a High-Affinity Competitive Antagonist of the Transient Receptor Potential Vanilloid 1 Receptor J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 791 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kissin, C. F. Freitas, and E. L. Bradley Jr Perineural Resiniferatoxin Prevents the Development of Hyperalgesia Produced by Loose Ligation of the Sciatic Nerve in Rats Anesth. Analg., May 1, 2007; 104(5): 1210 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Liedtke Hydromineral Neuroendocrinology: Role of TRPV ion channels in sensory transduction of osmotic stimuli in mammals Exp Physiol, May 1, 2007; 92(3): 507 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Gavva, A. W. Bannon, S. Surapaneni, D. N. Hovland Jr, S. G. Lehto, A. Gore, T. Juan, H. Deng, B. Han, L. Klionsky, et al. The Vanilloid Receptor TRPV1 Is Tonically Activated In Vivo and Involved in Body Temperature Regulation J. Neurosci., March 28, 2007; 27(13): 3366 - 3374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Liedtke Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli J. Endocrinol., December 1, 2006; 191(3): 515 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cui, P. Honore, C. Zhong, D. Gauvin, J. Mikusa, G. Hernandez, P. Chandran, A. Gomtsyan, B. Brown, E. K. Bayburt, et al. TRPV1 Receptors in the CNS Play a Key Role in Broad-Spectrum Analgesia of TRPV1 Antagonists. J. Neurosci., September 13, 2006; 26(37): 9385 - 9393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Gavva, R. Tamir, L. Klionsky, M. H. Norman, J.-C. Louis, K. D. Wild, and J. J. S. Treanor Proton Activation Does Not Alter Antagonist Interaction with the Capsaicin-Binding Pocket of TRPV1 Mol. Pharmacol., December 1, 2005; 68(6): 1524 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Hogestatt, B. A. G. Jonsson, A. Ermund, D. A. Andersson, H. Bjork, J. P. Alexander, B. F. Cravatt, A. I. Basbaum, and P. M. Zygmunt Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System J. Biol. Chem., September 9, 2005; 280(36): 31405 - 31412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Honore, C. T. Wismer, J. Mikusa, C. Z. Zhu, C. Zhong, D. M. Gauvin, A. Gomtsyan, R. El Kouhen, C.-H. Lee, K. Marsh, et al. A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a Novel Transient Receptor Potential Type V1 Receptor Antagonist, Relieves Pathophysiological Pain Associated with Inflammation and Tissue Injury in Rats J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 410 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Gavva, R. Tamir, Y. Qu, L. Klionsky, T. J. Zhang, D. Immke, J. Wang, D. Zhu, T. W. Vanderah, F. Porreca, et al. AMG 9810 [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with Antihyperalgesic Properties J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 474 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Rong, K. Hillsley, J. B Davis, G. Hicks, W. J Winchester, and D. Grundy Jejunal afferent nerve sensitivity in wild-type and TRPV1 knockout mice J. Physiol., November 1, 2004; 560(3): 867 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Gavva, L. Klionsky, Y. Qu, L. Shi, R. Tamir, S. Edenson, T. J. Zhang, V. N. Viswanadhan, A. Toth, L. V. Pearce, et al. Molecular Determinants of Vanilloid Sensitivity in TRPV1 J. Biol. Chem., May 7, 2004; 279(19): 20283 - 20295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Toth, P. M. Blumberg, Z. Chen, and A. P. Kozikowski Design of a High-Affinity Competitive Antagonist of the Vanilloid Receptor Selective for the Calcium Entry-Linked Receptor Population Mol. Pharmacol., February 1, 2004; 65(2): 282 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Valenzano, E. R. Grant, G. Wu, M. Hachicha, L. Schmid, L. Tafesse, Q. Sun, Y. Rotshteyn, J. Francis, J. Limberis, et al. N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 377 - 386. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
