Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine-1-receptor antagonists

PLoS One. 2013 Jun 12;8(6):e66884. doi: 10.1371/journal.pone.0066884. Print 2013.

Abstract

Background: The histamine-1 receptor (H1R) antagonist ketotifen increased the threshold of discomfort in hypersensitive IBS patients. The use of peripherally restricted and more selective H1R antagonists may further improve treatment possibilities. We examined the use of fexofenadine and ebastine to reverse post-stress visceral hypersensitivity in maternally separated rats.

Methods: The visceromotor response to colonic distension was assessed in adult maternally separated and nonhandled rats pre- and 24 hours post water avoidance. Subsequently rats were treated with vehicle alone or different dosages of fexofenadine (1.8 and 18 mg/kg) or ebastine (0.1 and 1.0 mg/kg) and re-evaluated. Colonic tissue was collected to assess relative RMCP-2 and occludin expression levels by Western blot and histamine-1 receptor by RT-qPCR. β-hexosaminidase release by RBL-2H3 cells was used to establish possible mast cell stabilizing properties of the antagonists.

Key results: Water avoidance only induced enhanced response to distension in maternally separated rats. This response was reversed by 1.8 and 18 mg/kg fexofenadine. Reversal was also obtained by 1.0 but not 0.1 mg/kg ebastine. RMCP-2 expression levels were comparable in these two ebastine treatment groups but occludin was significantly higher in 1.0 mg/kg treated rats. There were no differences in histamine-1 receptor expression between nonhandled and maternally separated rats. Fexofenadine but not ebastine showed mast cell stabilizing quality.

Conclusions: Our results indicate that the peripherally restricted 2(nd) generation H1-receptor antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rat. These data justify future IBS patient trials with these well tolerated compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Butyrophenones / pharmacology
  • Dose-Response Relationship, Drug
  • Histamine H1 Antagonists / pharmacology*
  • Irritable Bowel Syndrome / drug therapy*
  • Irritable Bowel Syndrome / etiology*
  • Mast Cells / drug effects
  • Maternal Deprivation*
  • Occludin / metabolism
  • Piperidines / pharmacology
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stress, Psychological / complications*
  • Terfenadine / analogs & derivatives
  • Terfenadine / pharmacology

Substances

  • Butyrophenones
  • Histamine H1 Antagonists
  • Occludin
  • Piperidines
  • Terfenadine
  • fexofenadine
  • ebastine

Grant support

OIS was supported by funding for the IPODD consortium under Grant Agreement 202020 of the Seventh Research Framework Programme of the European Union (http://www.IPODD.eu). SAvD was supported by the Netherlands Top Institute Pharma, grant number T1-215-1 (www.TIPharma.com) and the Netherlands Digestive Diseases Foundation (MLDS), project number WO10-12 (www.MLDS.NL/). ZY was supported by The China Exchange Programme (CEP) of the Royal Netherlands Academy of Arts and Sciences (KNAW), project number 11CDP005 (www.KNAW.NL). WJdJ was funded by a grant of the Dutch Organization for Scientific Research (NWO-VIDI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.