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.Key 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 & Inferences
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.
Endotoxin sensitizes intestinal afferent nerves in mice in vitro to 5-HT, bradykinin and mechanical ramp distension. This sensitization was dependent on mast cells and the COX-2 but not to the COX-1 pathway.