Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides.
BACKGROUND
The 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.


METHODS
The 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.


RESULTS
PF-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
These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, AB, Canada; Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
J
J
Fichna
M
M
Sałaga
J
J
Stuart
D
D
Saur
M
M
Sobczak
H
H
Zatorski
J-P
JP
Timmermans
H B
HB
Bradshaw
K
K
Ahn
M A
MA
Storr
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D003106:Colon / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D007082:Ileum / Q000378:metabolism; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D000930:Antidiarrheals; D063388:Endocannabinoids; D010880:Piperidines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C557973:PF 3845
anandamide; diarrhea-predominant irritable bowel syndrome; endocannabinoid system; fatty acid amide hydrolase; visceral pain