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Differential effects of CB1 neutral antagonists and inverse agonists on gastrointestinal motility in mice

Authors

  • M. A. Storr,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Division of Gastroenterology, Department of Medicine, University Calgary, Calgary, AB, Canada
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    • 1

      Author is currently: School of Pharmacy and Life Sciences, The Robert Gordon University, Aberdeen, Scotland.

  • M. Bashashati,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Hotchkiss Brain Institute, University Calgary, Calgary, AB, Canada
    3. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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  • C. Hirota,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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  • V. K. Vemuri,

    1. Center for Drug Discovery, Northeastern University, Boston, MA, USA
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  • C. M. Keenan,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Hotchkiss Brain Institute, University Calgary, Calgary, AB, Canada
    3. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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  • M. Duncan,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Hotchkiss Brain Institute, University Calgary, Calgary, AB, Canada
    3. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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    • 1

      Author is currently: School of Pharmacy and Life Sciences, The Robert Gordon University, Aberdeen, Scotland.

  • B. Lutz,

    1. Department of Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • K. Mackie,

    1. Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA
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  • A. Makriyannis,

    1. Center for Drug Discovery, Northeastern University, Boston, MA, USA
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  • W. K. Macnaughton,

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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  • K. A. Sharkey

    1. Snyder Institute of Infection, Immunity & Inflammation, University Calgary, Calgary, AB, Canada
    2. Hotchkiss Brain Institute, University Calgary, Calgary, AB, Canada
    3. Department of Physiology & Pharmacology, University Calgary, Calgary, AB, Canada
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Dr Martin Storr, MD, Division of Gastroenterology, Department of Medicine, University Calgary, 3280 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.
Tel: 403 592 5015; fax: 403 592 5090;
e-mail: mstorr@ucalgary.ca

Abstract

Background  Cannabinoid type 1 (CB1) receptors are involved in the regulation of gastrointestinal (GI) motility and secretion. Our aim was to characterize the roles of the CB1 receptor on GI motility and secretion in vitro and in vivo by using different classes of CB1 receptor antagonists.

Methods  Immunohistochemistry was used to examine the localization of CB1 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.

Key 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 & Inferences  Cannabinoid type 1 receptors regulate small intestinal and colonic motility, but not GI secretion under physiological conditions. Cannabinoid type 1 inverse agonists and CB1 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 CB1 receptor antagonists as therapeutic agents.

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