Publication
Title
Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides
Author
Abstract
BackgroundThe endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases. However, side effects of CB agonists prompted the search for novel therapeutic targets. Here, the effect of PF-3845, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor in the GI tract was investigated. MethodsThe effect of PF-3845 on GI motility was characterized in vitro and in vivo, using mouse models that mimic physiological and pathophysiological conditions. The antinociceptive action of PF-3845 was evaluated on the basis of behavioral pain models. Endocannabinoid degradation product levels after inhibition of FAAH were quantified using HPLC-MS/MS. Key ResultsPF-3845 significantly inhibited mouse colonic motility in vitro and in vivo. Selective inhibition of FAAH reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. The effects of PF-3845 were mediated by endogenous CBs and non-CB lipophilic compounds via classical (CB1) and atypical CB receptors. Conclusions & InferencesThese data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.
Language
English
Source (journal)
Neurogastroenterology and motility / European Gastrointestinal Motility Society. - Cambridge, Mass., 1994, currens
Publication
Cambridge, Mass. : 2014
ISSN
1350-1925 [print]
1365-2982 [online]
Volume/pages
26:4(2014), p. 470-481
ISI
000332984500003
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 12.05.2014
Last edited 16.07.2017
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