title: The endogenous cannabinoid system protects against colonic inflammation.
abstract: 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.
authors.affiliation: Group Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Massa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Heike
authors.initials: H
authors.lastname: Hermann
authors.forename: Astrid
authors.initials: A
authors.lastname: Cannich
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Gian-Luca
authors.initials: GL
authors.lastname: Ferri
authors.forename: Andrei
authors.initials: A
authors.lastname: Sibaev
authors.forename: Martin
authors.initials: M
authors.lastname: Storr
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000581:Amidohydrolases / Q000502:physiology; D000818:Animals; D003092:Colitis / Q000517:prevention & control*; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives*; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004139:Dinitrofluorobenzene; D013759:Dronabinol; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C045305:2,4-dinitrofluorobenzene sulfonic acid; C062018:HU 211