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

Neurogastroenterol Motil. 2012 Mar;24(3):274-82, e111. doi: 10.1111/j.1365-2982.2011.01840.x. Epub 2011 Nov 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chymases / metabolism
  • Colon / physiology
  • Corticotropin-Releasing Hormone / drug effects*
  • Electromyography
  • Female
  • Gastrointestinal Motility / physiology
  • Hormone Antagonists / pharmacology*
  • Hyperalgesia / physiopathology
  • Mast Cells / cytology
  • Mast Cells / drug effects*
  • Mast Cells / physiology*
  • Maternal Deprivation*
  • Peptide Fragments / drug effects*
  • Pregnancy
  • Rats
  • Rats, Long-Evans
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Stress, Psychological* / physiopathology
  • Stress, Psychological* / psychology
  • Visceral Pain / physiopathology*


  • Hormone Antagonists
  • Peptide Fragments
  • Receptors, Corticotropin-Releasing Hormone
  • Corticotropin-Releasing Hormone
  • corticotropin releasing hormone (9-41)
  • chymase 2
  • Chymases