title: Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity.
abstract: OBJECTIVE
  Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.
  
  
  METHODS
  Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.
  
  
  RESULTS
  Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.
  
  
  CONCLUSIONS
  H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Deiteren
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.
authors.forename: Joris G
authors.initials: JG
authors.lastname: De Man
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.
authors.forename: Nathalie E
authors.initials: NE
authors.lastname: Ruyssers
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium Department of Gastroenterology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Tom G
authors.initials: TG
authors.lastname: Moreels
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium Department of Gastroenterology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Pelckmans
authors.affiliation: Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.
authors.forename: Benedicte Y
authors.initials: BY
authors.lastname: De Winter
mesh_terms: D000818:Animals; D017332:Cetirizine / Q000494:pharmacology; D003092:Colitis / Q000150:complications / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D003113:Colonoscopy / Q000379:methods; D003289:Convalescence; D004195:Disease Models, Animal; D006632:Histamine / Q000378:metabolism; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D006636:Histamine Release / Q000502:physiology; D006967:Hypersensitivity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; C498828:Hrh4 protein, rat; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; C472067:levocetirizine; D006632:Histamine; D014302:Trinitrobenzenesulfonic Acid; D017332:Cetirizine
keywords: HISTAMINE; MAST CELLS; VISCERAL HYPERSENSITIVITY; VISCERAL NOCICEPTION