Abstract
Vanilloid receptor type 1 (VR1) (TRPV1) is a ligand-gated ion channel expressed on sensory nerves that responds to noxious heat, protons, and chemical stimuli such as capsaicin. Herein, we have examined the activity of the VR1 antagonist capsazepine in models of inflammatory and neuropathic pain in the rat, mouse, and guinea pig. In naı̈ve animals, subcutaneous administration of capsazepine (10–100 mg/kg s.c.) did not affect withdrawal thresholds to noxious thermal or mechanical stimuli. However, pretreatment with capsazepine prevented the development of mechanical hyperalgesia induced by intraplantar injection of capsaicin, with a similar potency in all three species. Capsazepine (up to 100 mg/kg s.c.) did not affect mechanical hyperalgesia in the Freund's complete adjuvant (FCA)-inflamed hind paw of the rat or mouse. Strikingly, capsazepine (3–30 mg/kg s.c.) produced up to 44% reversal of FCA-induced mechanical hyperalgesia in the guinea pig. Capsazepine also produced significant reversal of carageenan-induced thermal hyperalgesia in the guinea pig at 30 mg/kg s.c., but was ineffective in the rat. Similarly, in the partial sciatic nerve ligation model of neuropathic pain, capsazepine was surprisingly effective in the guinea pig, producing up to 80% reversal of mechanical hyperalgesia (1–30 mg/kg s.c.) but had no effect in the rat or mouse. These data show that VR1 antagonists have antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain, and illustrate species differences in the in vivo pharmacology of VR1 that correlate with differences in pharmacology previously seen in vitro.
Footnotes
-
↵1 Current address: Purdue Pharma, 6 Cedar Brooke Dr., Cranbury, NJ 08512.
-
↵2 Current address: GlaxoSmithKline Pharmaceuticals Ltd., Harlow, UK.
-
The experiments in this manuscript have previously been reported in abstract form at the 2001 meeting of the Society for Neuroscience (Walker K, Gentry C, Medhurst S, Patel S, Panesar M, Urban L, and McIntyre P (2001) Capsazepine shows species selective antihyperalgesic effects in models of chronic inflammatory and neuropathic pain. Soc Neurosci Abst31:926.7).
-
DOI: 10.1124/jpet.102.042010
- Abbreviations:
- VR1
- vanilloid receptor 1, TRPV1
- DRG
- dorsal root ganglion
- FCA
- Freund's complete adjuvant
- ANOVA
- analysis of variance
- HSD
- honestly significant difference
- Received July 19, 2002.
- Accepted September 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|