Involvement of cannabinoid CB2 receptors in the IgE-mediated cutaneous reaction was investigated. Epicutaneous challenge with 2,4-dinitrofluorobenzene caused a triphasic swelling in the ear of BALB/c and C57BL/6 mice passively sensitized with anti-dinitrophenol IgE. Peak responses of the ear swelling appeared at 1 h, 24 h, and 8 days after the challenge in both strains of mice. In contrast, cannabinoid CB2 receptor-deficient mice failed to exhibit the obvious triphasic ear swelling observed in wild-type mice. Oral administration of cannabinoid CB2 receptor antagonist/inverse agonists [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR144528) at doses of 0.1-10 mg/kg significantly and dose-dependently suppressed all three phases of ear swelling in BALB/c mice. Interestingly, epicutaneous treatment with an ether-linked analogue of endogenous cannabinoids, 2-arachidonoylglycerol, caused an ear swelling that could be detected at 1 h, 24 h, and 8 days after treatment of both BALB/c and C57BL/6 mice. These results suggest that cannabinoid CB2 receptors are involved in induction of the triphasic cutaneous reaction mediated by IgE, and that cannabinoid CB2 receptor antagonist/inverse agonists may serve as anti-allergic agents in the treatment of allergic dermatitis.