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THE CANNABINOID-2 (CB₂) RECEPTOR AGONIST AM1241 MEDIATES PROTECTION AGAINST TNBS COLITIS IN MICE

M Storr, C Keenan, K Patel, K Sharkey
Department of Physiology and Biophysics and Division of Gastroenterology, Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta

BACKGROUND: The endocannabinoid-system has been reported to be involved in intestinal inflammation. Activation of cannabinoid-1 (CB₁) receptors results in attenuation of experimental colitis. However, little is known about the possible influence of the CB₂ receptor in intestinal inflammation.
AIM: Our aim was to describe the effects of a selective CB₂ receptor agonist (AM1241) and a CB₂ receptor antagonist (AM630) in experimentally induced, trinitrobenzene sulfonic acid (TNBS), colitis in wildtype mice and CB₂ receptor deficient mice.
METHODS: Colitis was induced in male C57BL/6 mice by intra-rectal installation of 100 µl 4% TNBS in 30% ethanol. Weight changes were observed for 3 days. At day 3, the mice were sacrificed and the colon was removed for macroscopic scoring and the evaluation of myeloperoxidase (MPO) activity. 6-10 mice in each group were treated with intraperitoneal injections of the CB₂ receptor agonist AM1241 (10-20mg/kg) or the CB₂ antagonist AM630 (10mg/kg) once daily or vehicle.
RESULTS: Intrarectal installation of TNBS caused marked colonic inflammation. TNBS treated mice had a macroscopic score of 8.5 ± 1.4 compared to 0.9 ± 0.3 in the vehicle (ethanol) treated control mice. TNBS treated mice showed a MPO level of 5.9 ± 2.4 U/mg compared to 0.7 ± 0.6 U/mg in the vehicle control mice. The CB₂ receptor agonist AM1241 reduced the macroscopic score (10mg: 3.3 ± 0.4; 20mg: 3.2 ± 0.5) and MPO levels (10mg: 1.3 ± 0.9 U/mg; 20mg: 0.3 ± 0.1 U/mg) in a dose-dependent manner. In contrast, the CB₂ receptor antagonist AM630 caused a significant increase in inflammation (macroscopic score: 8.9 ± 0.5; MPO level: 6.4 ± 2.6 U/mg). Body weight changes and survival rates were not significantly different amongst treatment groups. In CB₂ receptor deficient mice AM1241 had no protective effect.
CONCLUSION: This study provides evidence that activation of the CB₂ receptor reduces colonic inflammation under experimental conditions suggesting that the CB₂ receptor may be a possible therapeutic target in inflammatory bowel disease.
Alberta Heritage Foundation for Medical Research, Crohn’s and Colitis Foundation of Canada and Canadian Institutes of Health Research

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