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Peripheral α-helical CRF (9-41) does not reverse stress-induced mast cell dependent visceral hypersensitivity in maternally separated rats

Authors

  • R. M. van den Wijngaard,

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
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    • These authors contributed equally to this work.

  • O. I. Stanisor,

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
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    • These authors contributed equally to this work.

  • S. A. van Diest,

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
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  • O. Welting,

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
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  • M. M. Wouters,

    1. Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
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  • W. J. de Jonge,

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
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  • G. E. Boeckxstaens

    1. Tytgat Institute for Liver and Intestinal research, Academic Medical Center, Amsterdam, The Netherlands
    2. Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
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Address for Correspondence
René M van den Wijngaard, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Room S2-180, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands.
Tel: +31 020 566 8163; fax: +31 020 566 9190;
e-mail: r.vandenwijngaard@amc.uva.nl

Abstract

Background  Acute stress-induced hypersensitivity to colorectal distention was shown to depend on corticotropin releasing factor (CRF)-induced mast cell degranulation. At present it remains unclear whether CRF also induces chronic poststress activation of these cells. Accordingly, the objective of this study was to compare pre- and poststress CRF-receptor antagonist treatment protocols for their ability to, respectively, prevent and reverse mast cell dependent visceral hypersensitivity in a rat model of neonatal maternal separation.

Methods  The visceromotor response to colonic distention was assessed in adult maternally separated and non-handled rats before and at different time points after 1 h of water avoidance (WA). Rats were treated with the mast cell stabilizer doxantrazole and the CRF receptor-antagonist α-helical-CRF (9-41). Western blotting was used to assess mucosal protein levels of the mast cell protease RMCP-2 and the tight junction protein occludin.

Key Results  In maternally separated, but not in non-handled rats, WA induced chronic hypersensitivity (up to 30 days) to colorectal distention. Visceral hypersensitivity was prevented, but could not be reversed by administration of α-helical-CRF (9-41). In contrast, however, the mast cell stabilizer doxantrazole reversed visceral hypersensitivity. Compared with vehicle-treated rats, pre-WA α-helical-CRF (9-41) treated animals displayed higher mucosal RMCP-2 and occludin levels.

Conclusions & Inferences  Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.

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