title: Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity.
abstract: OBJECTIVE
  Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB1/2 ). Because the CB1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we determined whether defective 2-AG degradation affects μ-opioid receptor (μ receptor) signalling, a parallel pathway regulating gut motility.
  
  
  METHODS
  Gut motility was investigated by monitoring Evans Blue transit and colonic bead propulsion in response to MGL inhibition and CB1 receptor or μ receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB1 receptor expression in ileum and colon was assessed by immunohistochemical analyses.
  
  
  RESULTS
  Pharmacological inhibition of MGL slowed down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels. Notably, MGL deficiency caused complete insensitivity to CB1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB1 receptors were trapped in endocytic vesicles. Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility. This phenotype was reproduced by chronic pharmacological inhibition of MGL.
  
  
  CONCLUSIONS
  Constantly elevated 2-AG levels induce severe desensitization of intestinal CB1 receptors and increased sensitivity to μ receptor-mediated inhibition of colonic motility. These changes should be considered when cannabinoid-based drugs are used in the therapy of gastrointestinal diseases.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: U
authors.initials: U
authors.lastname: Taschler
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: T O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: F P W
authors.initials: FP
authors.lastname: Radner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: G F
authors.initials: GF
authors.lastname: Grabner
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Storr
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Schicho
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D001212:Asialoglycoproteins / Q000172:deficiency*; D002186:Cannabinoids / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000502:physiology; D007082:Ileum / Q000378:metabolism*; D037181:Lectins, C-Type / Q000172:deficiency*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001212:Asialoglycoproteins; D002186:Cannabinoids; C064720:Clec10a protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D043884:Receptor, Cannabinoid, CB1; D017450:Receptors, Opioid, mu