title: Ex vivo study of human visceral nociceptors.
abstract: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation.
  
  
  
  Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses.
  
  
  
  Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity.
  
  
  
  Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Cian
authors.initials: C
authors.lastname: McGuire
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: George
authors.initials: G
authors.lastname: Boundouki
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: James R F
authors.initials: JRF
authors.lastname: Hockley
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Reed
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cibert-Goton
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Madusha
authors.initials: M
authors.lastname: Peiris
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Kung
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Broad
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Qasim
authors.initials: Q
authors.lastname: Aziz
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chan
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Shafi
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Thaha
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Sanger
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Blackshaw
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Knowles
authors.affiliation: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Bulmer
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007422:Intestines / Q000187:drug effects / Q000294:innervation*; D009025:Morpholines / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D010812:Physical Stimulation / Q000379:methods; D011758:Pyrroles / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D046509:Tissue Culture Techniques
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D005765:Gastrointestinal Agents; C573308:HC-067047; D007211:Indoles; D009025:Morpholines; D011758:Pyrroles; C120984:R 715; D017366:Serotonin Receptor Agonists; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C105050:tegaserod; C065679:icatibant; D000255:Adenosine Triphosphate; D001920:Bradykinin
keywords: ABDOMINAL PAIN; ELECTROPHYSIOLOGY; NEUROGASTROENTEROLOGY; VISCERAL NOCICEPTION; VISCERAL SENSITIVITY