title: Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice.
abstract: OBJECTIVE
  Gastrointestinal (GI) motility is regulated in part by fatty acid ethanolamides (FAEs), including the endocannabinoid (EC) anandamide (AEA). The actions of FAEs are terminated by fatty acid amide hydrolase (FAAH). We investigated the actions of the novel FAAH inhibitor AM3506 on normal and enhanced GI motility.
  
  
  METHODS
  We examined the effect of AM3506 on electrically-evoked contractility in vitro and GI transit and colonic faecal output in vivo, in normal and FAAH-deficient mice treated with saline or LPS (100 µg·kg(-1), i.p.), in the presence and absence of cannabinoid (CB) receptor antagonists. mRNA expression was measured by quantitative real time-PCR, EC levels by liquid chromatography-MS and FAAH activity by the conversion of [(3)H]-AEA to [(3)H]-ethanolamine in intestinal extracts. FAAH expression was examined by immunohistochemistry.
  
  
  RESULTS
  FAAH was dominantly expressed in the enteric nervous system; its mRNA levels were higher in the ileum than the colon. LPS enhanced ileal contractility in the absence of overt inflammation. AM3506 reversed the enhanced electrically-evoked contractions of the ileum through CB(1) and CB(2) receptors. LPS increased the rate of upper GI transit and faecal output. AM3506 normalized the enhanced GI transit through CB(1) and CB(2) receptors and faecal output through CB(1) receptors. LPS did not increase GI transit in FAAH-deficient mice.
  
  
  CONCLUSIONS
  Inhibiting FAAH normalizes various parameters of GI dysmotility in intestinal pathophysiology. Inhibition of FAAH represents a new approach to the treatment of disordered intestinal motility.
authors: Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity & Inflammation, Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada.
authors: M
authors: M
authors: Bashashati
authors: M A
authors: MA
authors: Storr
authors: S P
authors: SP
authors: Nikas
authors: J T
authors: JT
authors: Wood
authors: G
authors: G
authors: Godlewski
authors: J
authors: J
authors: Liu
authors: W
authors: W
authors: Ho
authors: C M
authors: CM
authors: Keenan
authors: H
authors: H
authors: Zhang
authors: S O
authors: SO
authors: Alapafuja
authors: B F
authors: BF
authors: Cravatt
authors: B
authors: B
authors: Lutz
authors: K
authors: K
authors: Mackie
authors: G
authors: G
authors: Kunos
authors: K D
authors: KD
authors: Patel
authors: A
authors: A
authors: Makriyannis
authors: J S
authors: JS
authors: Davison
authors: K A
authors: KA
authors: Sharkey
mesh_terms: D000476:Alkanesulfonates / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology*; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010636:Phenols / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000476:Alkanesulfonates; D000581:Amidohydrolases; D004731:Endotoxins; D008070:Lipopolysaccharides; D010636:Phenols; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C556520:AM 3506