1. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain.
- Author
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Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, and McIntyre P
- Subjects
- Algorithms, Animals, Anticonvulsants pharmacology, Carbamazepine pharmacology, Dose-Response Relationship, Drug, Guinea Pigs, Hyperalgesia etiology, Hyperalgesia pathology, Inflammation etiology, Inflammation pathology, Male, Mice, Mice, Inbred C57BL, Peripheral Nervous System Diseases complications, Peripheral Nervous System Diseases pathology, Rats, Rats, Wistar, Sciatic Nerve pathology, Capsaicin analogs & derivatives, Capsaicin pharmacology, Hyperalgesia drug therapy, Inflammation drug therapy, Peripheral Nervous System Diseases drug therapy, Receptors, Drug antagonists & inhibitors
- 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 naïve 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.
- Published
- 2003
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