title: Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation.
abstract: The deleterious effects of stress on the gastrointestinal tract seem to be mainly mediated by the induction of intestinal barrier dysfunction and subsequent subtle mucosal inflammation. Cannabinoid 1 receptor (CB1R) is expressed in the mammalian gut under physiological circumstances. The aim of this investigation is to study the possible role of CB1R in the maintenance of mucosal homeostasis after stress exposure. CB1R knockout mice (CB1R(-/-)) and their wild-type (WT) counterparts were exposed to immobilization and acoustic (IA) stress for 2 h per day during 4 consecutive days. Colonic protein expression of the inducible forms of the nitric oxide synthase and cyclooxygenase (NOS2 and COX2), IgA production, permeability to (51)Cr-EDTA, and bacterial translocation to mesenteric lymph nodes were evaluated. Stress exposure induced greater expression of proinflammatory enzymes NOS2 and COX2 in colonic mucosa of CB1R(-/-) mice when compared with WT animals. These changes were related with a greater degree of colonic barrier dysfunction in CB1R(-/-) animals determined by 1) a significantly lower IgA secretion, 2) higher paracellular permeability to (51)Cr-EDTA, and 3) higher bacterial translocation, both under basal conditions and after IA stress exposure. Pharmacological antagonism with rimonabant reproduced stress-induced increase of proinflammatory enzymes in the colon described in CB1R(-/-) mice. In conclusion, CB1R exerts a protective role in the colon in vivo through the regulation of intestinal secretion of IgA and paracellular permeability. Pharmacological modulation of cannabinoid system within the gastrointestinal tract might be therapeutically useful in conditions on which intestinal inflammation and barrier dysfunction takes place after exposure to stress.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zoppi
authors.forename: José L M
authors.initials: JL
authors.lastname: Madrigal
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Pérez-Nievas
authors.forename: Ignacio
authors.initials: I
authors.lastname: Marín-Jiménez
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.forename: Arturo
authors.initials: A
authors.lastname: Colón
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Gómez-Lus
authors.forename: Luis
authors.initials: L
authors.lastname: Menchén
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology; D002860:Chromium Radioisotopes / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004492:Edetic Acid / Q000378:metabolism; D007070:Immunoglobulin A / Q000378:metabolism; D007413:Intestinal Mucosa / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010539:Permeability; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000502:physiology*; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000503:physiopathology; D014465:Ultrasonics
chemical_list: D002860:Chromium Radioisotopes; D007070:Immunoglobulin A; D043884:Receptor, Cannabinoid, CB1; D004492:Edetic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2