title: Modulation of intestinal afferent nerve sensitivity to inflammatory mediators following systemic endotoxin in mice.
abstract: BACKGROUND
  Endotoxin exposure may be followed by visceral hypersensitvity but potential mechanisms are not fully explored. We aimed to test the hypothesis that mast cells and the cyclooxygenase pathway (COX) mediate modulation of afferent nerve sensitivity following systemic endotoxin.
  
  
  METHODS
  C57Bl6 mice received endotoxin injection i.p. to induce systemic inflammation. Control animals received normal saline. Extracellular multi-unit afferent nerve discharge was recorded from jejunal mesenteric nerves in vitro. Afferent nerve response to 5-hydroxytryptamine (5-HT, 250 μmol/L), bradykinin (BK, 0.5 μmol/L), and to mechanical ramp distension of the intestinal lumen from 0 to 60 cmH2O were recorded 2 h following endotoxin administration.
  
  
  RESULTS
  Following endotoxin administration peak afferent discharge to 5-HT and BK was increased compared to controls (p < 0.05). Pre-perfusion with the mast cell stabilizer Doxantrazole (10(-4) M), or the cyclooxygenase inhibitor Naproxen inhibited the increased response to 5-HT and BK (p < 0.05 vs endotoxin pretreatment). Mechanosensitivity during luminal ramp distension from 10 to 60 cmH2O was increased following endotoxin pretreatment compared to controls (p < 0.05). This increase in sensitivity following endotoxin was no longer observed after Doxantrazole or Naproxen administration for pressures from 10 to 30 cmH2O (p < 0.05). Selective COX-2 inhibition by NS398 (10 μM) but not COX-1 inhibition by SC560 (300 μM) reduced increased afferent discharge in endotoxin pretreated animals to 5-HT, BK and mechanical ramp distension from 10 to 40 cmH2O (all p < 0.05).
  
  
  CONCLUSIONS
  Systemic endotoxin sensitizes mesenteric afferent nerve fibers to 5-HT, BK and mechanical stimuli. The underlying mechanism responsible for this sensitization seems to involve mast cells and the COX-2 pathway.
authors: Department of Pathophysiology, Medical School, Shandong University, Jinan, China; Department of Surgery, Ludwig-Maximilians University, Munich, Germany.
authors: B
authors: B
authors: Xue
authors: M S
authors: MS
authors: Kasparek
authors: M H
authors: MH
authors: Müller
authors: M E
authors: ME
authors: Kreis
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000294:innervation* / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010812:Physical Stimulation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013892:Thioxanthenes / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D013892:Thioxanthenes; D044004:Xanthones; D012701:Serotonin; D011451:Prostaglandin-Endoperoxide Synthases; D001920:Bradykinin; C010134:doxantrazole
keywords: COX-2; afferent nerve; endotoxin; mast cell; visceral sensitivity