FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF1 agonist mediated visceral hypersensitivity in male rats.
Muriel Larauche, Agata Mulak, Chrysanthy Ha, Mulugeta Million, Stacy Arnett, Peter Germano, James P Pearson, Mark G Currie, Yvette Taché
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引用次数: 0
Abstract
Background and aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF1) agonist, cortagine.
Methods: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.
Key results: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. URB597 did not modify cortagine-induced defecation/diarrhea versus vehicle.
Conclusions and inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity.
期刊介绍：
Neurogastroenterology & Motility (NMO) is the official Journal of the European Society of Neurogastroenterology & Motility (ESNM) and the American Neurogastroenterology and Motility Society (ANMS). It is edited by James Galligan, Albert Bredenoord, and Stephen Vanner. The editorial and peer review process is independent of the societies affiliated to the journal and publisher: Neither the ANMS, the ESNM or the Publisher have editorial decision-making power. Whenever these are relevant to the content being considered or published, the editors, journal management committee and editorial board declare their interests and affiliations.
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