title: Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine-1-receptor antagonists.
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.
  
  
  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.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Oana I
authors.initials: OI
authors.lastname: Stanisor
authors.forename: Sophie A
authors.initials: SA
authors.lastname: van Diest
authors.forename: Zhumei
authors.initials: Z
authors.lastname: Yu
authors.forename: Olaf
authors.initials: O
authors.lastname: Welting
authors.forename: Noor
authors.initials: N
authors.lastname: Bekkali
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.forename: Rene M
authors.initials: RM
authors.lastname: van den Wijngaard
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002090:Butyrophenones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000209:etiology*; D008407:Mast Cells / Q000187:drug effects; D008426:Maternal Deprivation; D062793:Occludin / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000150:complications*; D016593:Terfenadine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D062793:Occludin; D010880:Piperidines; D016593:Terfenadine; C093230:fexofenadine; C058249:ebastine