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BEHAVIORAL PHARMACOLOGY

Selective Activation of Cannabinoid CB₂ Receptors Suppresses Hyperalgesia Evoked by Intradermal Capsaicin

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, Georgia (A.G.H, J.N.F.); and Departments of Pharmaceutical Sciences and Molecular and Cell Biology and Center for Drug Discovery, University of Connecticut, Storrs, Connecticut (A.M.Z., A.M.)

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-3-yl]-methanone (AM1241) (33, 330 µg/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 µg/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.

Address correspondence to: Dr. Andrea G. Hohmann, Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013. E-mail: ahomann{at}uga.edu

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