Abstract
The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.083915.
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ABBREVIATIONS: TRPV1, transient receptor potential type V1; CFA, complete Freund's adjuvant; A-425619, 1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; DRG, dorsal root ganglion; PWL, paw withdrawal latency; PWT, paw withdrawal threshold; MIA, monoiodoacetate; WBD, weight-bearing difference; CNS, central nervous system; SB-366791, SN-(3-methoxyphenyl)-4-chlorocinnamide; compound 41, 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethyl pyridin-2-yl)amide; AMG9810, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo-[b][1,4]dioxin-6-yl)acrylamide.
- Received January 21, 2005.
- Accepted April 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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