The present studies were conducted to test the hypothesis that activation of peripheral
cannabinoid CB(2) receptors would suppress
hyperalgesia evoked by intradermal administration of
capsaicin, the pungent ingredient in hot chili peppers. The CB(2)-selective
cannabinoid agonist (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indol-3-yl]-methanone (
AM1241) (33, 330 microg/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 CB(2) 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 CB(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (
SR141716A).
AM1241 (33 microg/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 CB(2) receptors are sufficient to normalize nociceptive thresholds and produce antinociception in persistent
pain states.