title: Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome.
abstract: OBJECTIVE
  Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial.
  
  
  METHODS
  By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension.
  
  
  RESULTS
  TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004).
  
  
  CONCLUSIONS
  In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Mira M
authors.initials: MM
authors.lastname: Wouters
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Dafne
authors.initials: D
authors.lastname: Balemans
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Sander
authors.initials: S
authors.lastname: Van Wanrooy
authors.affiliation: Autoimmune Genetics Laboratory, Flemish Institute for Biotechnology (VIB) and Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Centre for Neuroscience and Trauma, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cibert-Goton
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research and Transient Receptor Potential (TRP) channel Research Platform, KU Leuven, Leuven, Belgium.
authors.forename: Yeranddy A
authors.initials: YA
authors.lastname: Alpizar
authors.affiliation: Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Canada.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Valdez-Morales
authors.affiliation: Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Canada.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Nasser
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Lipid Biochemistry and Protein-Interaction, KU Leuven, Leuven, Belgium.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Winde
authors.initials: W
authors.lastname: Vanbrabant
authors.affiliation: Department of Clinical and Experimental Medicine, Hepatology, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Schalk
authors.initials: S
authors.lastname: Van der Merwe
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link (Vesalius Research Center), KU Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Carla
authors.initials: C
authors.lastname: Cirillo
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Kortekaas
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link (Vesalius Research Center), KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Department of Internal Medicine, Laboratory for Clinical Infectious and Inflammatory Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Willy E
authors.initials: WE
authors.lastname: Peetermans
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium; Department of Otorhinolaryngology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands; Department of Otorhinolaryngology, University of Ghent, Ghent, Belgium.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hellings
authors.affiliation: Department of Biostatistics and Centre of Statistical Bioinformatics, KU Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Belmans
authors.affiliation: Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Vanner
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Centre for Neuroscience and Trauma, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Bulmer
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research and Transient Receptor Potential (TRP) channel Research Platform, KU Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Talavera
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vanden Berghe
authors.affiliation: Autoimmune Genetics Laboratory, Flemish Institute for Biotechnology (VIB) and Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, KU Leuven, Leuven, Belgium. Electronic address: guy.boeckxstaens@med.kuleuven.be.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
mesh_terms: D015746:Abdominal Pain / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D000293:Adolescent; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use*; D001530:Belgium; D001706:Biopsy; D002090:Butyrophenones / Q000009:adverse effects / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D020239:Receptor Cross-Talk / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D012007:Rectum / Q000294:innervation*; D012074:Remission Induction; D011795:Surveys and Questionnaires; D050916:TRPV Cation Channels / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000700:Analgesics; D002090:Butyrophenones; D005765:Gastrointestinal Agents; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C058249:ebastine
keywords: Drug; Sensory Neurons; Transient Receptor Potential Cation Channel Subfamily V Member 1; Treatment