title: Repeated water avoidance stress induces visceral hypersensitivity: Role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor.
abstract: OBJECTIVE
  Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue.
  
  
  METHODS
  Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress.
  
  
  RESULTS
  Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 μg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 μg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 μg/kg) ip for two times before the measurement abolished the response.
  
  
  CONCLUSIONS
  Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.
authors.affiliation: Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Nozu
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Miyagishi
authors.affiliation: Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Nozu
authors.affiliation: Research Center for Brain Function and Medical Engineering, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Takakusaki
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Okumura
mesh_terms: D000009:Abdominal Muscles / Q000503:physiopathology; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology; D007375:Interleukin-1 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D008407:Mast Cells; D009119:Muscle Contraction; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications*; D014781:Viscera
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D003346:Corticotropin-Releasing Hormone
keywords: corticotropin-releasing factor; cytokine; mast cell; repeated water avoidance stress; visceral allodynia