title: Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain.
abstract: BACKGROUND
  Activation of proteinase-activated receptor-4 (PAR-4) from the colonic lumen has an antinociceptive effect to colorectal distension (CRD) in mice in basal conditions. We aimed to determine the functional localization of the responsible receptors and to test their role in two different hyperalgesia models.
  
  
  METHODS
  Mice received PAR-4 activating peptide (PAR-4-AP, AYPGKF-NH(2)) or vehicle intraperitoneally (IP), and abdominal EMG response to CRD was measured. The next group received PAR-4-AP intracolonically (IC) with or without 2,4,6-triaminopyrimidine, a chemical tight junction blocker, before CRD. The SCID mice were used to test the role of lymphocytes in the antihyperalgesic effect. The effects of PAR-4-AP and PAR-4-antagonist (P4pal-10) were evaluated in water avoidance stress (WAS) model and low grade 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis. Spinal Fos protein expression was visualized by immunohistochemistry.
  
  
  RESULTS
  The antinociceptive effect of PAR-4-AP disappeared when was administrered IP, or with the blockade of colonic epithelial tight junctions, suggesting that PAR-4-AP needs to reach directly the nerve terminals in the colon. The CRD-induced spinal Fos overexpression was reduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesic in both hyperalgesia models and in mice with impaired lymphocytes. The PAR-4-antagonist significantly increased the TNBS, but not the WAS-induced colonic hyperalgesia.
  
  
  CONCLUSIONS
  The antinociceptive effect of PAR-4-AP depends on its penetration to the colonic mucosa. The PAR-4 activation is endogenously involved as a feedback loop to attenuate inflammatory colonic hyperalgesia to CRD.
authors: Toxalim UMR 1331 INRA/INP/UPS Neuro-Gastroenterology & Nutrition Unit, Toulouse, France.
authors: A
authors: A
authors: Annaházi
authors: M
authors: M
authors: Dabek
authors: K
authors: K
authors: Gecse
authors: C
authors: C
authors: Salvador-Cartier
authors: A
authors: A
authors: Polizzi
authors: A
authors: A
authors: Rosztóczy
authors: R
authors: R
authors: Róka
authors: V
authors: V
authors: Theodorou
authors: T
authors: T
authors: Wittmann
authors: L
authors: L
authors: Bueno
authors: H
authors: H
authors: Eutamene
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D004108:Dilatation, Pathologic; D004576:Electromyography; D025461:Feedback, Physiological / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D059265:Visceral Pain / Q000503:physiopathology*
chemical_list: C482003:AYPGKG-NH(2); D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; D018179:Receptors, Thrombin; D014302:Trinitrobenzenesulfonic Acid; C112908:protease-activated receptor 4