Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation.
1. We have studied the effect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal inflammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2-arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states. 2. CP 55,940 (0.03 - 10 nmol mouse(-1)) and cannabinol (10 - 3000 nmol mouse(-1)) were more active in delaying intestinal motility in croton oil-treated mice than in control mice. These inhibitory effects were counteracted by the selective cannabinoid CB(1) receptor antagonist SR141716A (16 nmol mouse(-1)). SR141716A (1 - 300 nmol mouse(-1)), administered alone, increased intestinal motility to the same extent in both control and croton oil-treated mice. 3. Croton oil-induced intestinal inflammation was associated with an increased expression of CB(1) receptor, an unprecedented example of up-regulation of cannabinoid receptors during inflammation. 4. High levels of anandamide and 2-arachidonylglycerol were detected in the small intestine, although no differences were observed between control and croton oil-treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the inflamed small intestine. 5. It is concluded that inflammation of the gut increases the potency of cannabinoid agonists possibly by 'up-regulating' CB(1) receptor expression; in addition, endocannabinoids, whose turnover is increased in inflamed gut, might tonically inhibit intestinal motility.
Izzo
A A
AA
Department of Experimental Pharmacology, University of Naples "Federico II", via D. Montesano 49, 80131 Naples Italy. aaizzo@unina.it
Fezza
F
F
Capasso
R
R
Bisogno
T
T
Pinto
L
L
Iuvone
T
T
Esposito
G
G
Mascolo
N
N
Di Marzo
V
V
Capasso
F
F
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000819:agonists / Q000378:metabolism*; D002187:Cannabinol / Q000494:pharmacology / Q000627:therapeutic use; D003436:Croton Oil; D003511:Cyclohexanols / Q000494:pharmacology / Q000627:therapeutic use; D003879:Dermatologic Agents; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D000077285:Rimonabant
D000700:Analgesics; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D003511:Cyclohexanols; D003879:Dermatologic Agents; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D002187:Cannabinol; D003436:Croton Oil; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant