Efficacy of ABT-116, an antagonist of transient receptor potential vanilloid type 1, in providing analgesia for dogs with chemically induced synovitis

Curtis J. Cathcart Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Spencer A. Johnston Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Lisa R. Reynolds Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Sami Al-Nadaf Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Steven C. Budsberg Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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DOI:
https://doi.org/10.2460/ajvr.73.1.19
Volume/Issue:
Volume 73: Issue 1
Online Publication Date:
01 Jan 2012
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Abstract

Objective—To investigate the ability of ABT-116 (a proprietary antagonist of transient receptor potential vanilloid type 1) administered at 2 doses to attenuate lameness in dogs with experimentally induced urate synovitis.

Animals—8 purpose-bred mixed-breed dogs.

Procedures—In a 4-way crossover study, dogs orally received each of low-dose ABT-116 treatment (LDA; 10 mg/kg), high-dose ABT-116 treatment (HDA; 30 mg/kg), firocoxib (5 mg/kg), and no treatment (nontreatment) once a day for 2 days, in a randomly assigned order. Synovitis was induced on the second day of each treatment period by intra-articular injection of either stifle joint with sodium urate, alternating between joints for each treatment period, beginning with the left stifle joint. Ground reaction forces, clinical lameness scores, and rectal temperature were assessed before the injection (baseline) and at various points afterward.

Results—Lameness scores at the 2-, 6-, and 12-hour assessment points were higher than baseline scores for HDA and nontreatment, whereas scores at the 2- and 6-hour points were higher than baseline scores for LDA. For firocoxib, there was no difference from baseline scores in lameness scores at any point. Compared with baseline values, peak vertical force and vertical impulse were lower at 2 and 6 hours for HDA and nontreatment and at 2 hours for LDA. No changes in these values were evident for firocoxib. The HDA or LDA resulted in higher rectal temperatures than did treatment with firocoxib or nothing, but those temperatures did not differ among treatments.

Conclusions and Clinical Relevance—HDA had no apparent effect on sodium urate–induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern.

Abstract

Objective—To investigate the ability of ABT-116 (a proprietary antagonist of transient receptor potential vanilloid type 1) administered at 2 doses to attenuate lameness in dogs with experimentally induced urate synovitis.

Animals—8 purpose-bred mixed-breed dogs.

Procedures—In a 4-way crossover study, dogs orally received each of low-dose ABT-116 treatment (LDA; 10 mg/kg), high-dose ABT-116 treatment (HDA; 30 mg/kg), firocoxib (5 mg/kg), and no treatment (nontreatment) once a day for 2 days, in a randomly assigned order. Synovitis was induced on the second day of each treatment period by intra-articular injection of either stifle joint with sodium urate, alternating between joints for each treatment period, beginning with the left stifle joint. Ground reaction forces, clinical lameness scores, and rectal temperature were assessed before the injection (baseline) and at various points afterward.

Results—Lameness scores at the 2-, 6-, and 12-hour assessment points were higher than baseline scores for HDA and nontreatment, whereas scores at the 2- and 6-hour points were higher than baseline scores for LDA. For firocoxib, there was no difference from baseline scores in lameness scores at any point. Compared with baseline values, peak vertical force and vertical impulse were lower at 2 and 6 hours for HDA and nontreatment and at 2 hours for LDA. No changes in these values were evident for firocoxib. The HDA or LDA resulted in higher rectal temperatures than did treatment with firocoxib or nothing, but those temperatures did not differ among treatments.

Conclusions and Clinical Relevance—HDA had no apparent effect on sodium urate–induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern.

Multimodal pain control including modulation of inflammation, suppression of afferent pain pathways, and neuronal transmission inhibition has been advocated.1–4 Classes of drugs studied for potential benefit as centrally acting analgesics include opioids,1 neurokinin-1 receptor antagonists,5,6 cyclooxygenase inhibitors,1,7 and vanilloid receptor antagonists.8,9 Vanilloid receptor antagonists have the additional benefit of peripheral sensory blockade, preventing initiation of nociceptive signals.10

Vanilloid receptors or, more specifically, TRPV1s are part of the diverse transient receptor potential su-perfamily of receptors. In mammals, receptors in this superfamily are responsible for a range of functions, including fertility, epithelial growth, vision, taste, olfaction, osmosensation and mechanosensation, and noci-ception.11,12 The TRPV1 alone is involved in physiologic functions and pathological conditions of the brain, inner ear, skin, gastrointestinal tract, urinary tract, airways, and circulatory system,13 in addition to the widely investigated area of nociception.14,15 It functions as a ligand-gated nonselective cation channel, contributing substantially to regulation of intracellular calcium concentrations.16 A TRPV1 can be activated by endogenous vanilloids, exogenous vanilloids, heat (> 43°C), and low pH.17,18 Additionally, expression of TRPV1s is upregulated in an inflammatory environment as well as with certain neuropathies, which suggests a role in neuropathic pain and inflammatory hyperalgesia.16

Interestingly, analgesia can be attained by both agonism and antagonism of TRPV1s.19 Potent agonists such as capsaicin (used in discovery of the receptor eventually called TRPV1)17 have an initial excitatory effect followed by a desensitization phase that is refractory to further noxious stimulation.18,20 Concern exists in some clinical settings regarding possible permanent neurotoxic effects caused by potent agonists.14,21 Wide variability of therapeutic effects and responses has been seen with numerous TRPV1 agonists as well as antagonists.19 Antagonist administration can reportedly attenuate thermal hyperalgesia, pain associated with bone cancer, and arthritic pain.22

The purpose of the study reported here was to examine the ability of 2 doses of the vanilloid receptor antagonist ABT-116 to attenuate lameness associated with stifle joint urate synovitis in dogs. The hypotheses were that LDA would be more effective at attenuating the lameness than a negative control treatment, HDA would be more effective at attenuating the lameness than the negative control treatment, and HDA would be more effective at attenuating the lameness than LDA.

Materials and Methods

Animals—Eight skeletally mature purpose-bred mixed-breed dogs (4 males and 4 females) ranging in body weight from 16.5 to 27.5 kg and aged 6 to 10 years (median, 7) were used in the study. All dogs underwent physical and orthopedic examinations as well as radiographic evaluation of the hip and stifle joints. Dogs were excluded from the study when there was any evidence of lameness or health concerns.

All dogs were housed within a climate-controlled animal housing facility in individual runs (1.2 × 2.4 m), received routine vaccinations and anthelmintics, were fed a commercially available maintenance diet, and were offered water ad libitum. The study protocol was approved by the University of Georgia Institutional Animal Care and Use Committee.

Study design—A blinded 4-way crossover study design was used, with all dogs receiving all treatments only once and a minimum 21-day washout period observed between each treatment. Power calculations revealed that in a crossover design, a sample size of 8 would allow detection of a 5% change in vertical GRF measurements and 10% change in craniocaudal values. The treatment order was assigned randomly for each dog.a Treatments included LDA (10 mg/kg, PO), HDA (30 mg/kg, PO), firocoxibb (5 mg/kg, PO; positive control), and no treatment (nontreatment). Treatments were administered once daily in the morning for 2 days (days 0 and 1). Day 0 treatments were administered 2 hours after a meal, and day 1 (day of SU injection) treatments were given before feeding, 1 hour before SU injection. Dogs were fed immediately upon return to their runs, after recovery from SU injection. They were then observed in their runs every 15 minutes for 2 hours, at which point they were continually observed for the next 2 hours as well as at 2-hour intervals corresponding to each assessment point. Any adverse event observed at any assessment point during the study was recorded.

Lameness induction—On day 1, dogs were briefly anesthetized with propofolc (6 mg/kg, IV). Synovitis was induced by intra-articular injection into the stifle joint of 1.0 mL of a 10.0 mg/mL solution of SU prepared as described elsewhere.23 Injection sites alternated between the left and right stifle joints of each dog, beginning with the left joint for the first treatment and ending with right joint for the last treatment. Each dog was kept in a large dog crate on the day of testing and was walked for 10 minutes 4 times daily. During the SU challenge, any dog that had a subjective clinical lameness score ≥ 13 (Appendix) or had signs of pain (eg, vocalization after anesthetic recovery or dramatic behavioral changes after SU injection) was to be deemed in excessive pain, immediately withdrawn from the study, and given an NSAID or opioid as necessary until those signs were no longer evident.

Lameness assessment—One observer (CJC), who played no role in treatment randomization, dose calculation, or treatment administration and was unaware of treatment assignment throughout the entire study, evaluated GRFs and performed a clinical lameness evaluation on day 1 before SU injection (baseline) and 2, 6, 12, and 24 hours after SU injection. Rectal temperature was recorded at the same points, before dogs were trotted on the force platform, and before propofol anesthesia.

Clinical lameness scoring was also performed at the same points for each dog by use of a subjective lameness scoring system (Appendix).24 Ground reaction force data were collected with 2 force platesd mounted in series, a dedicated computer, and software.e From the GRF data, PVF, VI, PCBF, CBI, PCPF, and CPI were determined. All trials were performed at a trotting speed of 1.70 to 2.10 m/s and an acceleration and deceleration of 0.50 m/s2. Each dog was trotted by the same handler for all periods of the experiment. Trials were only accepted when there was a single hind limb footfall on each force platform and a standard trotting gait was maintained with no extraneous movements by the dog or handler. At each assessment point for each dog, 5 observations were recorded for both hind limbs (healthy and SU-injected stifles).

Statistical analysis—Normality of data distribution was confirmed with the Kolmogorov-Smirnov test. A repeated-measures model to account for multiple observations per dog was used to test differences in outcome measurements (PVF, VI, PCBF, CBI, PCPF, CPI, subjective lameness scores, and rectal temperature) between treatments and over time. The full model included factors for treatment, time, and treatment-by-time interaction. Multiple comparisons were adjusted for by use of a Tukey test. An unstructured covariance matrix was used in all repeated-measures models. All hypothesis tests were 2-sided, and values of P < 0.05 were considered significant. All analyses were performed by use of statistical software.f

Results

Animals—No adverse effects were evident during the study in any of the 8 dogs. Consistent moderate lameness was produced in each dog after lameness induction with no treatment (negative control). No dog was removed from the study for signs of excessive pain or discomfort.

Lameness scores—Lameness scores at 2, 6, and 12 hours after SU injection were significantly higher than baseline when the dogs received no treatment and when they received HDA (Figure 1). When dogs received LDA, these scores were significantly higher than baseline at 2 and 6 hours. Treatment with firocoxib yielded no difference in lameness score from baseline at any assessment point; however, nontreatment yielded significantly higher lameness scores than firocoxib at 2, 6, and 12 hours. Other between-treatment comparisons revealed significantly higher scores at 2 hours after SU injection for LDA versus firocoxib. Scores for HDA did not differ from scores for nontreatment at any time point but were significantly higher than scores for firocoxib at 2 and 6 hours.

Figure 1—
Figure 1—

Mean ± SE cumulative lameness scores at various points for dogs with experimentally induced stifle joint synovitis (n = 8) that orally received each of LDA (10 mg/kg), HDA (30 mg/kg), firocoxib (5 mg/kg), or no treatment (negative control) once a day for 2 days in a crossover study. Negative control values that differ significantly (P < 0.05) from score before synovitis induction (baseline; asterisks) and firocoxib value (tildes) are indicated. Values for HDA that differ significantly from the respective firocoxib value (crosses) and baseline (number signs) as well as values for LDA that differ significantly from baseline (plus signs) are also indicated.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

PVF—Compared with baseline values, PVFs at 2 and 6 hours after SU injection were significantly lower for nontreatment and HDA in dogs, whereas the PVF at 2 hours was significantly lower for LDA (Figure 2; Table 1). No differences from baseline were evident for firocoxib at any measurement point. Between-treatment comparisons yielded significantly higher PVFs for firocoxib versus nontreatment and HDA at 2 and 6 hours and for firocoxib versus LDA at 2 hours. Considering both types of ABT-116 treatment, only LDA resulted in a significantly greater PVF than for nontreatment at 6 hours after SU injection.

Figure 2—
Figure 2—

Mean ± SE PVF data (%BW) at various points for the dogs in Figure 1. Values for LDA that differ significantly (P < 0.05) from the respective firocoxib value (squares) and negative control value (diamonds) are indicated. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

Table 1—

Mean ± SD GRFs (peak forces, %BW; impulse, %BW × seconds) at various points for dogs with experimentally induced synovitis (n = 8) that orally received each of LDA (10 mg/kg), HDA (30 mg/kg), firocoxib (5 mg/kg), or no treatment (negative control) once a day for 2 days in a crossover study.
VariableBaseline2 h6 h12 h24 h
PVF     
 Negative control80.341 ± 4.0612.401 ± 22.964*a22.954 ± 32.370*a66.531 ± 12.14476.340 ± 4.497
 Firocoxib83.505 ± 5.10477.784 ± 10.58182.090 ± 6.26982.988 ± 7.25981.037 ± 6.279
 LDA80.463 ± 3.02136.140 ± 39.257*b67.459 ± 17.500d76.985 ± 10.11280.162 ± 5.489
 HDA82.768 ± 5.83722.789 ± 31.688*c47.501 ± 31.360*c63.435 ± 27.72277.613 ± 6.961
VI     
 Negative control9.527 ± 0.6561.541 ± 2.858*a2.895 ± 4.232*a8.175 ± 1.5489.216 ± 0.857
 Firocoxib9.921 ± 0.4389.310 ± 0.83210.082 ± 0.39410.270 ± 0.3519.842 ± 0.369
 LDA9.516 ± 0.7874.440 ± 4.878*b8.087 ± 2.236d9.139 ± 0.5679.410 ± 0.672
 HDA9.788 ± 0.8622.693 ± 3.718*c5.859 ± 3.946*c7.830 ± 3.4139.465 ± 0.762
PCBF     
 Negative control6.324 ± 1.5551.236 ± 2.296*a2.031 ± 2.972*a4.396 ± 1.1845.856 ± 1.521
 Firocoxib7.093 ± 1.8737.073 ± 2.0256.973 ± 2.2426.766 ± 1.8667.190 ± 1.801
 LDA6.504 ± 1.6293.410 ± 3.730b5.882 ± 1.502d6.083 ± 1.4186.212 ± 1.543
 HDA7.085 ± 0.9282.694 ± 4.098*c4.155 ± 3.2105.513 ± 3.1896.561 ± 1.748
CBI     
 Negative control0.205 ± 0.1050.029 ± 0.054*a0.063 ± 0.101a0.105 ± 0.0460.186 ± 0.114
 Firocoxib0.264 ± 0.1110.244 ± 0.1260.259 ± 0.1450.243 ± 0.1080.267 ± 0.121
 LDA0.230 ± 0.0680.095 ± 0.117b0.166 ± 0.0750.187 ± 0.0920.213 ± 0.085
 HDA0.256 ± 0.1000.090 ± 0.165*c0.117 ± 0.1010.173 ± 0.1330.209 ± 0.105
PCPF     
 Negative control10.244 ± 2.1351.949 ± 3.615*a3.308 ± 4.667*a9.512 ± 1.5719.516 ± 1.442
 Firocoxib9.580 ± 1.3739.256 ± 1.6869.798 ± 1.6989.790 ± 1.8839.132 ± 1.907
 LDA9.703 ± 0.7864.448 ± 4.774*b8.801 ± 2.363d9.530 ± 1.7619.641 ± 1.305
 HDA9.542 ± 1.2093.305 ± 4.704*c6.445 ± 4.0397.924 ± 3.4099.447 ± 1.602
CPI     
 Negative control0.841 ± 0.2110.197 ± 0.364*a0.311 ± 0.435*a0.837 ± 0.1340.785 ± 0.165
 Firocoxib0.728 ± 0.0850.748 ± 0.1270.804 ± 0.1540.796 ± 0.1300.728 ± 0.157
 LDA0.766 ± 0.0880.392 ± 0.4210.728 ± 0.1960.769 ± 0.1290.759 ± 0.102
 HDA0.732 ± 0.1390.300 ± 0.437*c0.575 ± 0.3780.661 ± 0.2980.755 ± 0.114

Treatment values are significantly (P < 0.05) different from respective baseline values.

Negative control value differs significantly (P < 0.05) from firocoxib value.

Low-dose ABT-116 treatment value differs significantly from firocoxib value.

High-dose ABT-116 treatment value differs significantly from firocoxib value.

Low-dose ABT-116 treatment value differs significantly from negative control value.

High-dose ABT-116 treatment value differs significantly from negative control value.

VI—Vertical impulse mirrored PVF with regard to significant differences at the same assessment times in that rather than being greater than baseline values as described for PVFs, VIs were less than baseline values (Figure 3; Table 1). Again, no differences from baseline were evident for firocoxib treatment at any point. Results of between-treatment comparisons indicated identical patterns as for PVF.

Figure 3—
Figure 3—

Mean ± SE VI force data (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

PCBF—Results of comparisons with baseline PCBFs were similar to those for VIs for HDA and non-treatment (Figure 4; Table 1). The PCBFs for LDA and for firocoxib did not differ from baseline at any measurement point. Between-treatment comparisons revealed significantly higher PCBFs at 2 hours after SU injection for firocoxib versus LDA and HDA as well as significantly higher PCBFs for firocoxib versus nontreatment at 2 and 6 hours. At 6 hours after SU injection, the PCBF for LDA was higher than for non-treatment.

Figure 4—
Figure 4—

Mean ± SE PCBF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

CBI—Compared with baseline values, CBIs for HDA and nontreatment were significantly lower at 2 hours after SU injection. Again, LDA and firocoxib yielded no difference from baseline CBIs at any measurement point (Figure 5; Table 1). Between-treatment comparisons revealed significantly higher CBIs at 2 hours after SU injection for firocoxib versus LDA and HDA as well as significantly higher CBIs at 2 and 6 hours for firocoxib versus nontreatment.

Figure 5—
Figure 5—

Mean ± SE CBI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

PCPF—Compared with baseline values, PCPFs for nontreatment were significantly lower at 2 and 6 hours after SU injection and values for HDA and LDA were significantly lower at 2 hours (Figure 6; Table 1). No differences from baseline were evident for firocoxib at any measurement points. Between-treatment comparisons revealed significantly higher PCPFs for firocoxib versus HDA and LDA at 2 hours and for firocoxib versus nontreatment at 2 and 6 hours. The PCPF at 6 hours after SU injection for LDA was also significantly higher than the nontreatment value at that point.

Figure 6—
Figure 6—

Mean ± SE PCPF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

CPI—Compared with baseline values, craniocaudal propulsion forces were significantly lower for non-treatment at 2 and 6 hours after SU injection and for HDA at 2 hours. No differences from baseline were evident for LDA or firocoxib treatment at any measurement point (Figure 7; Table 1). Between-treatment comparisons revealed significantly higher craniocaudal propulsion forces for firocoxib versus nontreatment at 2 and 6 hours and for firocoxib versus HDA (not LDA) at 2 hours. The craniocaudal propulsion forces were significantly higher for LDA than for nontreatment at 6 hours.

Figure 7—
Figure 7—

Mean ± SE CPI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

Rectal temperature—Rectal temperature data were compared within and between treatments at all assessment points (Figure 8). Temperature did not vary significantly from baseline when dogs received no treatment or firocoxib. However, values for LDA were significantly higher than baseline at 1, 2, and 24 hours after SU injection and those for HDA were higher than baseline at 1, 2, and 6 hours, reaching values as high as 39.7°C. Between-treatment comparisons revealed no significant differences between any pair of treatments at baseline. There were no significant temperature differences between nontreatment and firocoxib at any point. For LDA, rectal temperatures were higher than nontreatment values at 1, 2, 12, and 24 hours and higher than firocoxib values at all points after baseline. Values for HDA were significantly higher than nontreatment and firocoxib values at all points after baseline. At no time was there a significant difference between rectal temperatures for LDA and HDA.

Figure 8—
Figure 8—

Mean ± SE rectal temperature at various points for the dogs in Figure 1. Values for HDA that differ significantly (P < 0.05) from the negative control value are indicated (double crosses). See Figures 1 and 2 for remainder of key.

Citation: American Journal of Veterinary Research 73, 1; 10.2460/ajvr.73.1.19

Discussion

The SU synovitis model used in the present study resulted in a consistent lameness in dogs that resolved within 24 hours after SU injection as determined on the basis of lameness scores and GRFs. For each dog evaluated, GRFs at the start of each trial period did not differ and subjective clinical lameness scores were 0 for all baseline measures for all dogs. The SU dose and resulting lameness in the present study are similar to the dose and lameness previously reported.5,24 All treatments in the present study were given before SU was injected to preempt the pain response, and thus our results may differ from those achieved by administration after a noxious stimulus is initiated.

The first hypothesis (that LDA would be more effective at attenuating the lameness than nontreatment) was accepted because when dogs received LDA, a significant attenuation of limb dysfunction caused by the SU-induced stifle synovitis was noticed. This attenuation was brief and mild and became evident through differences in objective force plate values between LDA and nontreatment at 6 hours after SU injection. The second hypothesis (that HDA would be more effective at attenuating the lameness than non-treatment) was rejected because when dogs received HDA, there was no similar, significant attenuation of limb dysfunction. The third hypothesis (that HDA would be more effective at attenuating the lameness than LDA) was also rejected because of the lack of evidence to support it.

No difference existed between LDA and HDA for any comparison in the study. Interestingly, although not nearly as efficacious as firocoxib treatment at attenuating lameness in the SU model of inflammatory pain, LDA had a measurable effect, unlike HDA. Although elucidation of the reason ABT-116 had less of an effect at the higher dose selected was beyond the scope of this study, this apparently incongruous result is not an uncommon finding and could be explained by upregula-tion of gene expression of certain factors25 or by mixed agonist-antagonist effects.26

Although drugs acting on TRPV1s do not have mixed agonist-antagonist action, the induced effect may be nociceptive or antinociceptive, depending on location of the stimulated TRPV1s.15 Intracerebroventricu-lar injection of TRPV1 antagonists results in increased nociceptive thresholds,27,28 yet agonism of TRPV1s in the locus coeruleus results in antinociception.29,30 Likewise, capsaicin injected into periaqueductal gray region, which contains descending antinociceptive pathways, elicits analgesia mediated through stimulation of glutamate and N-methyl-d-aspartate receptors.31 More research is needed to provide insight into factors affecting the balance of nociception versus analgesia related to TRPV1 modulation.

The efficacy of various TRPV1 antagonists may be related to their CNS absorption. A comparison in rats of 2 TRPV1 antagonists, 1 with poor and 1 with good CNS penetration, showed reductions of thermal hyperalgesia and mechanical allodynia in inflammatory and osteoarthritic pain models that were correlated with CNS penetration.8 Different TRPV1 antagonists can also vary in their degree of blockade to activation by capsaicin, heat, and an environmental pH of 5.19 In addition to drug differences, human data reveal individual differences of drug effect on the basis of gender, ethnicity, and temperament.32

The most commonly reported effect of TRPV1 antagonist administration is attenuation of thermal hyperalgesia,10,17,33–36 with fewer reports10 of attenuation of chemical hyperalgesia. It is generally accepted that mechanical nociception is not modulated through TRPV1s.36,37 In the present study, attenuation of lameness was not profound at either dose of ABT-116 evaluated. This may have been attributable to lack of efficacy of ABT-116, but it may also be that TRPV1-modulated nociception does not play a large role in the SU-induced synovitis model in dogs. Similar models (intraplantar complete Freund adjuvant in rats) have revealed the efficacy of TRPV1 antagonists,8 but it is not known whether the SU-induced synovitis model in dogs creates an environment that would sensitize TRPV1s. Such changes include low pH, tissue temperature > 43°C, and presence of endovanilloids (including products of lipoxygenase [12-HPETE and 15-S-HPETE]).15

The intra-articular temperature associated with SU-induced synovitis is not known in dogs. One study38 involving rabbits revealed an increase in intra-articular temperature by 0.8°C after urate injection. In that study,38 isometric exercise decreased intra-articular temperature by 0.1°C and passive range of motion increased it by 1.6°C. If similar change occurs in the canine model, then intra-articular temperature would still be < 43°C, which is the reported threshold of TRPV1 sensitization.15

High body temperature, an undesirable effect of TRPV1 antagonists, was associated with administration of ABT-116 in the present study. The mechanism of TRPV1 antagonist-derived hyperthermia is believed to be related to peripheral vasoconstriction.39 Previous studies41 in dogs showed that administration of the TRPV1 antagonists with the most profound impact on body temperatures resulted in increases of up to 1.2°C. This was consistent with findings of the present study, in which there were mean rectal temperature increases of up to 1.2°C for LDA and up to 1.1°C for HDA. Although repeated dosing can attenuate this hyperthermia effect of TRPV1 antagonists,41 increases of this magnitude with ABT-116 administration may be of clinical concern. A study39 of a TRPV1 antagonist in humans revealed that the highest temperature increase was on day 1 of administration, but body temperatures remained significantly greater than those in subjects that received a placebo, as long as subjects were receiving daily doses. In addition, some subjects that received only 1 dose had persistent hyperthermia lasting for days, and this temperature increase was not completely reversed with acetaminophen administration.39

One limitation of the present study was the possibility of a type II error due to the low number of dogs per treatment. However, power calculations conducted prior to the study and a previous investigation24 in which the SU-induced synovitis model was used (n = 6 subjects/treatment) to evaluate meloxicam suggest that the potential of a type II error was low. Although there were no significant differences between LDA and HDA or HDA and nontreatment, measurements at many time points appeared to suggest higher GRFs and lower lameness scores for LDA versus HDA and for HDA versus no treatment.

In the present study, the efficacy of ABT-116 was poor, relative to that of the positive control, firocoxib, which suggests it would not be appropriate for use alone as an analgesic for acute arthritic conditions. Because of significant differences in efficacy and effects on body temperature among TRPV1 antagonists, TRPV1 antagonists as a class of drug warrant further investigation for their potential role as analgesics or as adjunct analgesics. Promise has also been shown in experimental models in which administration of TRPV1 agonists caused longer-lasting analgesia.14,19

ABBREVIATIONS

%BW

Percentage of body weight

CBI

Craniocaudal braking impulse

CPI

Craniocaudal propulsion impulse

GRF

Ground reaction force

HDA

High-dose ABT-116 treatment

LDA

Low-dose ABT-116 treatment

PCBF

Peak craniocaudal braking force

PCPF

Peak craniocaudal propulsion force

PVF

Peak vertical force

SU

Sodium urate

TRPV1

Transient receptor potential vanilloid type 1

VI

Vertical impulse
a.

Randomization plan generator, Dallal GE. Available at: www.randomization.com. Accessed Nov 17, 2008.

b.

Previcox, Merial Ltd, Duluth, Ga.

c.

Abbott Laboratories, North Chicago, Ill.

d.

Model OR-6-6, Advanced Mechanical Technology Inc, Newton, Mass.

e.

Acquire, version 7.3, Sharon Software, East Lansing, Mich.

f.

PROC MIXED, SAS, version 9.2, SAS Institute Inc, Cary, NC.

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    • Export Citation
  • 4.

    Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract 2008; 38:1173–1186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Punke JP, Speas AL, Reynolds LR, et al. Kinetic gait and subjective analysis of the effects of a tachykinin receptor antagonist in dogs with sodium urate-induced synovitis. Am J Vet Res 2007; 68:704–708.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hong SK, Han JS, Min SS, et al. Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat. Neurosci Lett 2002; 322:21–24.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    McCrory CR, Lindahl SG. Cyclooxygenase inhibition for postoperative analgesia. Anesth Analg 2002; 95:169–176.

  • 8.↑

    Cui M, Honore P, Zhong C, et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci 2006; 26:9385–9393.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Liu DL, Wang WT, Xing JL, et al. Research progress in transient receptor potential vanilloid 1 of sensory nervous system. Neurosci Bull 2009; 25:221–227.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.↑

    Garcia-Martinez C, Humet M, Planells-Cases R, et al. Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc Natl Acad Sci U S A 2002; 99:2374–2379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell 2002; 108:595–598.

  • 12.

    Bodo E, Biro T, Telek A, et al. A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am J Pathol 2005; 166:985–998.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.↑

    Nagy I, Santha P, Jancso G, et al. The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology. Eur J Pharmacol 2004; 500:351–369.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 agonist) therapy for pain relief: farewell or revival? Clin J Pain 2008; 24:142–154.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.↑

    Palazzo E, Rossi F, Maione S. Role of TRPV1 receptors in descending modulation of pain. Mol Cell Endocrinol 2008; 286:S79–S83.

  • 16.↑

    Cortright DN, Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur J Biochem 2004; 271:1814–1819.

  • 17.↑

    Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389:816–824.

  • 18.

    Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51:159–212.

  • 19.↑

    Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev 2009; 60:267–277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 2004; 38:377–384.

  • 21.

    Mozsik G, Vincze A, Szolcsanyi J. Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection. J Gastroenterol Hepatol 2001; 16:1093–1097.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.↑

    Szallasi A. Small molecule vanilloid TRPV1 receptor antagonists approaching drug status: can they live up to the expectations? Naunyn Schmiedebergs Arch Pharmacol 2006; 373:273–286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.↑

    Hamilton SM, Johnston SA, Broadstone RV. Evaluation of analgesia provided by the administration of epidural ketamine in dogs with a chemically induced synovitis. Vet Anaesth Analg 2005; 32:30–39.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.↑

    Cross AR, Budsberg SC, Keefe TJ. Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate-induced synovitis model in dogs. Am J Vet Res 1997; 58:626–631.

    • Search Google Scholar
    • Export Citation
  • 25.↑

    Niederberger E, Tegeder I, Vetter G, et al. Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-kappaB. FASEB J 2001; 15:1622–1624.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.↑

    Committee for Proprietary Medicinal Products. ICH Topic E 4—dose response information to support drug registration. London: European Medicines Agency, 1994.

    • Search Google Scholar
    • Export Citation
  • 27.

    Bodnar RJ, Kirchgessner A, Nilaver G, et al. Intraventricular capsaicin: alterations in analgesic responsivity without depletion of substance P. Neuroscience 1982; 7:631–638.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Bodnar RJ, Simone DA, Kordower JH, et al. Capsaicin treatment and stress-induced analgesia. Pharmacol Biochem Behav 1983; 18:65–71.

  • 29.

    Hajos M, Engberg G, Elam M. Reduced responsiveness of locus coeruleus neurons to cutaneous thermal stimuli in capsaicintreated rats. Neurosci Lett 1986; 70:382–387.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Hajos M, Jancso G, Engberg G. Capsaicin-induced excitation of locus coeruleus neurons. Acta Physiol Scand 1987; 129:415–420.

  • 31.↑

    Palazzo E, de Novellis V, Marabese I, et al. Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 2002; 439:69–75.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.↑

    Kim H, Neubert JK, San Miguel A, et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 2004; 109:488–496.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288:306–313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Moqrich A, Hwang SW, Earley TJ, et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 2005; 307:1468–1472.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Montell C. Thermosensation: hot findings make TRPNs very cool. Curr Biol 2003; 13:R476–R478.

  • 36.

    Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405:183–187.

  • 37.

    Jeffry JA, Yu SQ, Sikand P, et al. Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS One 2009; 4:e7021.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.↑

    Merritt JL, Hunder GG. Passive range of motion, not isometric exercise, amplifies acute urate synovitis. Arch Phys Med Rehabil 1983; 64:130–131.

    • Search Google Scholar
    • Export Citation
  • 39.↑

    Gavva NR, Treanor JJ, Garami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008; 136:202–210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Gavva NR, Bannon AW, Surapaneni S, et al. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J Neurosci 2007; 27:3366–3374.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.↑

    Gavva NR, Bannon AW, Hovland DN Jr, et al. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J Pharmacol Exp Ther 2007; 323:128–137.

    • Crossref
    • Search Google Scholar
    • Export Citation

Appendix

Description of scales used for subjective clinical lameness evaluation of dogs with urate-induced synovitis of a stifle joint.
ScoreDescription
Stance 
 0Clinically normal stance
 1Slightly abnormal stance (favors limb but foot remains on floor)
 2Severely abnormal stance (holds limb off floor)
 3Unable to stand
Lameness at a walk 
 0No lameness and full weight bearing observed on all strides; clinically normal gait
 1Mild subtle lameness with partial weight bearing; dog may bear full weight on some strides and not others
 2Obvious lameness with partial weight bearing; dog is clearly lame on all strides
 3Obvious lameness with intermittent weight bearing; dog is non–weight bearing on some strides and partial weight bearing on others (includes dogs that limp and have a slight lameness in which the dog will put weight on the limb sometimes but lean heavily on the nonlame limb [ie, toe touch lameness] on some strides)
 4Full non–weight bearing lameness; dog bears no weight on any strides
Lameness at a trot 
 0No lameness and full weight bearing observed on all strides; clinically normal gait
 1Mild subtle lameness with partial weight bearing; dog may bear full weight on some strides and not others
 2Obvious lameness with partial weight bearing; dog is clearly lame on all strides
 3Obvious lameness with intermittent weight bearing; dog is non–weight bearing on some strides and partial weight bearing on others (includes dogs with toe touch lameness on some strides)
 4Full non–weight bearing lameness; dog bears no weight on any strides
Signs of pain during manipulation of affected joint through its usual range of motion 
 0No signs of pain elicited on palpation or movement of affected joint
 1Mild signs of pain elicited (turns head in recognition) on palpation or movement of affected joint
 2Moderate signs of pain elicited (pulls limb away) on palpation or movement of affected joint
 3Severe signs of pain elicited on palpation or movement of affected joint (vocalizes, becomes aggressive, or will not allow palpation or movement of affected joint)

(Adapted from Punke JP, Speas AL, Reynolds LR, et al. Kinetic gait and subjective analysis of the effects of a tachykinin receptor antagonist in dogs with sodium urate–induced synovitis. Am J Vet Res 2007;68:704–708.)

Contributor Notes

Supported in part by Abbott Animal Health.

Address correspondence to Dr. Budsberg (budsberg@uga.edu).
Cover American Journal of Veterinary Research
American Journal of Veterinary Research
Publication Date:
01 Jan 2012
  • Figure 1—
    View in gallery
    Figure 1—

    Mean ± SE cumulative lameness scores at various points for dogs with experimentally induced stifle joint synovitis (n = 8) that orally received each of LDA (10 mg/kg), HDA (30 mg/kg), firocoxib (5 mg/kg), or no treatment (negative control) once a day for 2 days in a crossover study. Negative control values that differ significantly (P < 0.05) from score before synovitis induction (baseline; asterisks) and firocoxib value (tildes) are indicated. Values for HDA that differ significantly from the respective firocoxib value (crosses) and baseline (number signs) as well as values for LDA that differ significantly from baseline (plus signs) are also indicated.

  • Figure 2—
    View in gallery
    Figure 2—

    Mean ± SE PVF data (%BW) at various points for the dogs in Figure 1. Values for LDA that differ significantly (P < 0.05) from the respective firocoxib value (squares) and negative control value (diamonds) are indicated. See Figure 1 for remainder of key.

  • Figure 3—
    View in gallery
    Figure 3—

    Mean ± SE VI force data (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

  • Figure 4—
    View in gallery
    Figure 4—

    Mean ± SE PCBF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

  • Figure 5—
    View in gallery
    Figure 5—

    Mean ± SE CBI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

  • Figure 6—
    View in gallery
    Figure 6—

    Mean ± SE PCPF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

  • Figure 7—
    View in gallery
    Figure 7—

    Mean ± SE CPI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.

  • Figure 8—
    View in gallery
    Figure 8—

    Mean ± SE rectal temperature at various points for the dogs in Figure 1. Values for HDA that differ significantly (P < 0.05) from the negative control value are indicated (double crosses). See Figures 1 and 2 for remainder of key.

Figure 1—

Mean ± SE cumulative lameness scores at various points for dogs with experimentally induced stifle joint synovitis (n = 8) that orally received each of LDA (10 mg/kg), HDA (30 mg/kg), firocoxib (5 mg/kg), or no treatment (negative control) once a day for 2 days in a crossover study. Negative control values that differ significantly (P < 0.05) from score before synovitis induction (baseline; asterisks) and firocoxib value (tildes) are indicated. Values for HDA that differ significantly from the respective firocoxib value (crosses) and baseline (number signs) as well as values for LDA that differ significantly from baseline (plus signs) are also indicated.
Figure 2—

Mean ± SE PVF data (%BW) at various points for the dogs in Figure 1. Values for LDA that differ significantly (P < 0.05) from the respective firocoxib value (squares) and negative control value (diamonds) are indicated. See Figure 1 for remainder of key.
Figure 3—

Mean ± SE VI force data (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.
Figure 4—

Mean ± SE PCBF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.
Figure 5—

Mean ± SE CBI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.
Figure 6—

Mean ± SE PCPF (%BW) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.
Figure 7—

Mean ± SE CPI (%BW × seconds) at various points for the dogs in Figure 1. See Figures 1 and 2 for key.
Figure 8—

Mean ± SE rectal temperature at various points for the dogs in Figure 1. Values for HDA that differ significantly (P < 0.05) from the negative control value are indicated (double crosses). See Figures 1 and 2 for remainder of key.
  • 1.

    Christie MJ, Connor M, Vaughan CW, et al. Cellular actions of opioids and other analgesics: implications for synergism in pain relief. Clin Exp Pharmacol Physiol 2000; 27:520–523.

    • Crossref
    • Search Google Scholar
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  • 2.

    Kushiro T, Wiese AJ, Eppler MC, et al. Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res 2007; 68:1294–1299.

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  • 3.

    Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-d-aspartate receptor antagonists. J Am Vet Med Assoc 2006; 228:53–60.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Lamont LA. Multimodal pain management in veterinary medicine: the physiologic basis of pharmacologic therapies. Vet Clin North Am Small Anim Pract 2008; 38:1173–1186.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Punke JP, Speas AL, Reynolds LR, et al. Kinetic gait and subjective analysis of the effects of a tachykinin receptor antagonist in dogs with sodium urate-induced synovitis. Am J Vet Res 2007; 68:704–708.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Hong SK, Han JS, Min SS, et al. Local neurokinin-1 receptor in the knee joint contributes to the induction, but not maintenance, of arthritic pain in the rat. Neurosci Lett 2002; 322:21–24.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    McCrory CR, Lindahl SG. Cyclooxygenase inhibition for postoperative analgesia. Anesth Analg 2002; 95:169–176.

  • 8.

    Cui M, Honore P, Zhong C, et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci 2006; 26:9385–9393.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Liu DL, Wang WT, Xing JL, et al. Research progress in transient receptor potential vanilloid 1 of sensory nervous system. Neurosci Bull 2009; 25:221–227.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Garcia-Martinez C, Humet M, Planells-Cases R, et al. Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc Natl Acad Sci U S A 2002; 99:2374–2379.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell 2002; 108:595–598.

  • 12.

    Bodo E, Biro T, Telek A, et al. A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am J Pathol 2005; 166:985–998.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Nagy I, Santha P, Jancso G, et al. The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology. Eur J Pharmacol 2004; 500:351–369.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Knotkova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 agonist) therapy for pain relief: farewell or revival? Clin J Pain 2008; 24:142–154.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Palazzo E, Rossi F, Maione S. Role of TRPV1 receptors in descending modulation of pain. Mol Cell Endocrinol 2008; 286:S79–S83.

  • 16.

    Cortright DN, Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur J Biochem 2004; 271:1814–1819.

  • 17.

    Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389:816–824.

  • 18.

    Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51:159–212.

  • 19.

    Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev 2009; 60:267–277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 2004; 38:377–384.

  • 21.

    Mozsik G, Vincze A, Szolcsanyi J. Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection. J Gastroenterol Hepatol 2001; 16:1093–1097.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Szallasi A. Small molecule vanilloid TRPV1 receptor antagonists approaching drug status: can they live up to the expectations? Naunyn Schmiedebergs Arch Pharmacol 2006; 373:273–286.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Hamilton SM, Johnston SA, Broadstone RV. Evaluation of analgesia provided by the administration of epidural ketamine in dogs with a chemically induced synovitis. Vet Anaesth Analg 2005; 32:30–39.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Cross AR, Budsberg SC, Keefe TJ. Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate-induced synovitis model in dogs. Am J Vet Res 1997; 58:626–631.

    • Search Google Scholar
    • Export Citation
  • 25.

    Niederberger E, Tegeder I, Vetter G, et al. Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-kappaB. FASEB J 2001; 15:1622–1624.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Committee for Proprietary Medicinal Products. ICH Topic E 4—dose response information to support drug registration. London: European Medicines Agency, 1994.

    • Search Google Scholar
    • Export Citation
  • 27.

    Bodnar RJ, Kirchgessner A, Nilaver G, et al. Intraventricular capsaicin: alterations in analgesic responsivity without depletion of substance P. Neuroscience 1982; 7:631–638.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Bodnar RJ, Simone DA, Kordower JH, et al. Capsaicin treatment and stress-induced analgesia. Pharmacol Biochem Behav 1983; 18:65–71.

  • 29.

    Hajos M, Engberg G, Elam M. Reduced responsiveness of locus coeruleus neurons to cutaneous thermal stimuli in capsaicintreated rats. Neurosci Lett 1986; 70:382–387.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Hajos M, Jancso G, Engberg G. Capsaicin-induced excitation of locus coeruleus neurons. Acta Physiol Scand 1987; 129:415–420.

  • 31.

    Palazzo E, de Novellis V, Marabese I, et al. Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 2002; 439:69–75.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Kim H, Neubert JK, San Miguel A, et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 2004; 109:488–496.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288:306–313.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Moqrich A, Hwang SW, Earley TJ, et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 2005; 307:1468–1472.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Montell C. Thermosensation: hot findings make TRPNs very cool. Curr Biol 2003; 13:R476–R478.

  • 36.

    Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000; 405:183–187.

  • 37.

    Jeffry JA, Yu SQ, Sikand P, et al. Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS One 2009; 4:e7021.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Merritt JL, Hunder GG. Passive range of motion, not isometric exercise, amplifies acute urate synovitis. Arch Phys Med Rehabil 1983; 64:130–131.

    • Search Google Scholar
    • Export Citation
  • 39.

    Gavva NR, Treanor JJ, Garami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008; 136:202–210.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Gavva NR, Bannon AW, Surapaneni S, et al. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J Neurosci 2007; 27:3366–3374.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Gavva NR, Bannon AW, Hovland DN Jr, et al. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J Pharmacol Exp Ther 2007; 323:128–137.

    • Crossref
    • Search Google Scholar
    • Export Citation

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