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Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium

Enterology Research Team, Johnson and Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania

Submitted 31 August 2005 ; accepted in final form 23 March 2006

Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R)^–/– mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced (P < 0.05) colon weight gain (means ± SE; 82 ± 13% and 47 ± 15% inhibition, respectively), colon shrinkage (98 ± 24% and 42 ± 12%, respectively), colon inflammatory damage score (49 ± 11% and 40 ± 12%, respectively), and diarrhea (58 ± 12% and 43 ± 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited (P < 0.05) macroscopic and microscopic scores (46 ± 9% and 63 ± 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish (P < 0.05) macroscopic and microscopic scores (29 ± 7% and 43 ± 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.

allyl isothiocyanate; experimental inflammatory bowel disease; CB1R; CB2R; oil of mustard colitis

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