title: Differential effects of CB(1) neutral antagonists and inverse agonists on gastrointestinal motility in mice.
abstract: BACKGROUND
  Cannabinoid type 1 (CB(1)) receptors are involved in the regulation of gastrointestinal (GI) motility and secretion. Our aim was to characterize the roles of the CB(1) receptor on GI motility and secretion in vitro and in vivo by using different classes of CB(1) receptor antagonists.
  
  
  METHODS
  Immunohistochemistry was used to examine the localization of CB(1) receptor in the mouse ileum and colon. Organ bath experiments on mouse ileum and in vivo motility testing comprising upper GI transit, colonic expulsion, and whole gut transit were performed to characterize the effects of the inverse agonist/antagonist AM251 and the neutral antagonist AM4113. As a marker of secretory function we measured short circuit current in vitro using Ussing chambers and stool fluid content in vivo in mouse colon. We also assessed colonic epithelial permeability in vitro using FITC-labeled inulin.
  
  
  RESULTS
  In vivo, the inverse agonist AM251 increased upper GI transit and whole gut transit, but it had no effect on colonic expulsion. By contrast, the neutral antagonist AM4113 increased upper GI transit, but unexpectedly reduced both colonic expulsion and whole gut transit at high, but not lower doses.
  
  
  CONCLUSIONS
  Cannabinoid type 1 receptors regulate small intestinal and colonic motility, but not GI secretion under physiological conditions. Cannabinoid type 1 inverse agonists and CB(1) neutral antagonists have different effects on intestinal motility. The ability of the neutral antagonist not to affect whole gut transit may be important for the future development of CB(1) receptor antagonists as therapeutic agents.
authors.affiliation: Snyder Institute of Infection, Immunity & Inflammation, Division of Gastroenterology, Department of Medicine, University Calgary, Calgary, AB, Canada. mstorr@ucalgary.ca
authors.forename: M A
authors.initials: MA
authors.lastname: Storr
authors.forename: M
authors.initials: M
authors.lastname: Bashashati
authors.forename: C
authors.initials: C
authors.lastname: Hirota
authors.forename: V K
authors.initials: VK
authors.lastname: Vemuri
authors.forename: C M
authors.initials: CM
authors.lastname: Keenan
authors.forename: M
authors.initials: M
authors.lastname: Duncan
authors.forename: B
authors.initials: B
authors.lastname: Lutz
authors.forename: K
authors.initials: K
authors.lastname: Mackie
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: W K
authors.initials: WK
authors.lastname: Macnaughton
authors.forename: K A
authors.initials: KA
authors.lastname: Sharkey
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D007150:Immunohistochemistry; D007477:Ions / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000187:drug effects; D010539:Permeability; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077285:Rimonabant; D014867:Water / Q000032:analysis
chemical_list: C529765:AM4113; D007477:Ions; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014867:Water; C103505:AM 251; D000077285:Rimonabant