Title
Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amidesSelective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
Laboratory of cell biology and histology
Publication type
article
Publication
Cambridge, Mass.,
Subject
Human medicine
Source (journal)
Neurogastroenterology and motility / European Gastrointestinal Motility Society. - Cambridge, Mass., 1994, currens
Volume/pages
26(2014):4, p. 470-481
ISSN
1350-1925
1365-2982
ISI
000332984500003
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
E-info
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