Excessive inflammatory responses can emerge as a potential danger for organisms' health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that
cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of
2,4-dinitrobenzene sulfonic acid (
DNBS) and
oral administration of dextrane
sulfate sodium induced stronger
inflammation in CB1-deficient mice (CB1(-/-)) than in wild-type littermates (CB1(+/+)). Treatment of wild-type mice with the specific CB1 antagonist N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (
SR141716A) mimicked the phenotype of CB1(-/-) mice, showing an acute requirement of CB1 receptors for protection from
inflammation. Consistently, treatment with the
cannabinoid receptor agonist R(-)-7-hydroxy-Delta(6)-tetra-hydrocannabinol-dimethylheptyl (
HU210) or genetic ablation of the
endocannabinoid-degrading
enzyme fatty acid amide hydrolase (FAAH) resulted in protection against
DNBS-induced
colitis. Electrophysiological recordings from circular smooth muscle cells, performed 8 hours after
DNBS treatment, revealed spontaneous oscillatory action potentials in CB1(-/-) but not in CB1(+/+) colons, indicating an early CB1-mediated control of
inflammation-induced irritation of smooth muscle cells.
DNBS treatment increased the percentage of myenteric neurons expressing CB1 receptors, suggesting an enhancement of
cannabinoid signaling during
colitis. Our results indicate that the endogenous
cannabinoid system represents a promising therapeutic target for the treatment of
intestinal disease conditions characterized by excessive inflammatory responses.