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Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity.
Br J Pharmacol. 2015 Sep; 172(17):4419-29.BJ

Abstract

BACKGROUND AND PURPOSE

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.

EXPERIMENTAL APPROACH

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.

KEY 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.

CONCLUSION AND IMPLICATIONS

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+Show Affiliations

Institute of Molecular Biosciences, University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany.Institute of Molecular Biosciences, University of Graz, Graz, Austria.Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.Institute of Molecular Biosciences, University of Graz, Graz, Austria.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26075589

Citation

Taschler, U, et al. "Monoglyceride Lipase Deficiency Causes Desensitization of Intestinal Cannabinoid Receptor Type 1 and Increased Colonic Μ-opioid Receptor Sensitivity." British Journal of Pharmacology, vol. 172, no. 17, 2015, pp. 4419-29.
Taschler U, Eichmann TO, Radner FP, et al. Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity. Br J Pharmacol. 2015;172(17):4419-29.
Taschler, U., Eichmann, T. O., Radner, F. P., Grabner, G. F., Wolinski, H., Storr, M., Lass, A., Schicho, R., & Zimmermann, R. (2015). Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity. British Journal of Pharmacology, 172(17), 4419-29. https://doi.org/10.1111/bph.13224
Taschler U, et al. Monoglyceride Lipase Deficiency Causes Desensitization of Intestinal Cannabinoid Receptor Type 1 and Increased Colonic Μ-opioid Receptor Sensitivity. Br J Pharmacol. 2015;172(17):4419-29. PubMed PMID: 26075589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity. AU - Taschler,U, AU - Eichmann,T O, AU - Radner,F P W, AU - Grabner,G F, AU - Wolinski,H, AU - Storr,M, AU - Lass,A, AU - Schicho,R, AU - Zimmermann,R, Y1 - 2015/07/30/ PY - 2015/02/02/received PY - 2015/05/12/revised PY - 2015/06/03/accepted PY - 2015/6/16/entrez PY - 2015/6/16/pubmed PY - 2016/5/14/medline SP - 4419 EP - 29 JF - British journal of pharmacology JO - Br J Pharmacol VL - 172 IS - 17 N2 - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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. CONCLUSION AND IMPLICATIONS: 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/26075589/Monoglyceride_lipase_deficiency_causes_desensitization_of_intestinal_cannabinoid_receptor_type_1_and_increased_colonic_μ_opioid_receptor_sensitivity_ L2 - https://doi.org/10.1111/bph.13224 DB - PRIME DP - Unbound Medicine ER -