Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 308, Issue 2, Pages 446-453Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.103.060079
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- NIDA NIH HHS [DA9158, DA3801, DA14265, DA14022] Funding Source: Medline
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The present studies were conducted to test the hypothesis that activation of peripheral cannabinoid CB2 receptors would suppress hyperalgesia evoked by intradermal administration of capsaicin, the pungent ingredient in hot chili peppers. The CB2-selective cannabinoid agonist (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3yl]-methanone (AM1241) (33, 330 mug/kg i.p.) suppressed the development of capsaicin-evoked thermal and mechanical hyperalgesia and allodynia. AM1241 also produced a dose-dependent suppression of capsaicin-evoked nocifensive behavior. The AM1241-induced suppression of each parameter of capsaicin-evoked pain behavior was completely blocked by the CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicycle [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) but not by the CB1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A). AM1241 (33 mug/kg i.pl.) suppressed capsaicin-evoked thermal and mechanical hyperalgesia and allodynia after local administration to the capsaicin-treated (ipsilateral) paw but was inactive after administration to the capsaicin-untreated (contralateral) paw. Our data indicate that AM1241 suppresses capsaicin-evoked hyperalgesia and allodynia through a local site of action. These data provide evidence that actions at cannabinoid CB2 receptors are sufficient to normalize nociceptive thresholds and produce antinociception in persistent pain states.
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