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Modulation of intestinal afferent nerve sensitivity to inflammatory mediators following systemic endotoxin in mice
Author(s) -
Xue B.,
Kasparek M. S.,
Müller M. H.,
Kreis M. E.
Publication year - 2015
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.12531
Subject(s) - bradykinin , medicine , endocrinology , distension , cyclooxygenase , systemic administration , inflammation , chemistry , pharmacology , anesthesia , receptor , in vivo , biology , biochemistry , microbiology and biotechnology , enzyme
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 μ mol/L), bradykinin ( BK , 0.5 μ mol/L), and to mechanical ramp distension of the intestinal lumen from 0 to 60 cmH 2 O 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 cmH 2 O 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 cmH 2 O ( p < 0.05). Selective COX ‐2 inhibition by NS 398 (10 μ M) but not COX ‐1 inhibition by SC 560 (300 μ M) reduced increased afferent discharge in endotoxin pretreated animals to 5‐ HT , BK and mechanical ramp distension from 10 to 40 cmH 2 O (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.