title: Gut-derived cholecystokinin contributes to visceral hypersensitivity via nerve growth factor-dependent neurite outgrowth.
abstract: OBJECTIVE
  Irritable bowel syndrome is characterized by abdominal pain and altered bowel habits and may occur following stressful events or infectious gastroenteritis such as giardiasis. Recent findings revealed a link between cholecystokinin (CCK), neurotrophin synthesis, and intestinal hyperalgesia. The aim was to investigate the role of CCK in visceral hypersensitivity using mouse models challenged with a bout of infection with Giardia lamblia or psychological stress, either alone or in combination.
  
  
  METHODS
  Abdominal pain was evaluated by visceromoter response to colorectal distension. Nerve fibers in intestinal tissues were stained using immunohistochemistry (PGP9.5). Human neuroblastoma SH-SY5Y cells incubated with bacterial-free mouse gut supernatant or recombinant CCK-8S were assessed for neurite outgrowth and nerve growth factor (NGF) production.
  
  
  RESULTS
  Intestinal hypersensitivity was induced by either stress or Giardia infection, and a trend of increased pain was seen following dual stimuli. Increased CCK levels and PGP9.5 immunoreactivity were found in colonic mucosa of mice following stress and/or infection. Inhibitors to the CCK-A receptor (L-364718) or CCK-B receptor (L-365260) blocked visceral hypersensitivity caused by stress, but not when induced by giardiasis. Nerve fiber elongation and NGF synthesis were observed in SH-SY5Y cells after incubation with colonic supernatants from mice given the dual stimuli, or after treatment with CCK-8S. Increased nerve fiber length by colonic supernatant and CCK-8S was attenuated by L-365260 or neutralizing anti-NGF.
  
  
  CONCLUSIONS
  This new model successfully recapitulates intestinal hypernociception induced by stress or Giardia. Colonic CCK contributes to visceral hypersensitivity caused by stress, but not by Giardia, partly via NGF-dependent neurite outgrowth.
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kuan-Yang
authors.initials: KY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsiu-Wei
authors.initials: HW
authors.lastname: Wu
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Liu
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Meng-Ping
authors.initials: MP
authors.lastname: She
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tsung-Chun
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chin-Hung
authors.initials: CH
authors.lastname: Sun
authors.affiliation: Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Yu
authors.affiliation: Department of Biological Sciences, Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan. lchyu@ntu.edu.tw.
authors.forename: Linda Chia-Hui
authors.initials: LC
authors.lastname: Yu
mesh_terms: D015746:Abdominal Pain / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000494:pharmacology / Q000502:physiology*; D018920:Coculture Techniques; D003106:Colon / Q000294:innervation / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004106:Dilatation; D016829:Giardia lamblia; D005873:Giardiasis / Q000150:complications; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000294:innervation / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071446:Neuronal Outgrowth / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications
chemical_list: D017077:Culture Media, Conditioned; D011994:Recombinant Proteins; D002766:Cholecystokinin; D020932:Nerve Growth Factor
keywords: colon hyperalgesia; irritable bowel syndrome; neuroendocrine; post-giardiasis; psychological stress