Involvement of afferent neurons in the pathogenesis of endotoxin-induced ileus in mice: role of CGRP and TRPV1 receptors.
Activation of neuronal reflex pathways by inflammatory mediators is postulated as an important pathogenic mechanism in postoperative ileus. In this study, we investigated the involvement of afferent neurons and more specifically the role of the transient receptor potential vanilloid receptor type 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in endotoxin-induced motility disturbances in mice. Mice were injected with either lipopolysaccharides (LPS) or saline (control) and pre-treated with hexamethonium (blocker of neuronal transmission), capsaicin (neurotoxin), CGRP 8-37 (CGRP antagonist) or BCTC (TRPV1 receptor antagonist). We measured gastric emptying and intestinal transit of Evans blue next to rectal temperature and a global sickness behaviour scale. In vehicle-treated mice, LPS significantly delayed gastric emptying, small intestinal transit and rectal temperature while the sickness behaviour scale was increased. Hexamethonium, capsaicin, CGRP8-37 and BCTC all reversed the endotoxin-induced delay in gastric emptying and significantly reduced the delay in intestinal transit without effect on the endotoxin-induced decrease in rectal temperature and increase in sickness behaviour scale. Our findings provide evidence for the involvement of afferent nerves in the pathogenesis of endotoxin-induced motility disturbances in mice mediated via CGRP and TRPV1 receptors. Blockade of CGRP and TRPV1 receptors may offer a novel strategy for the treatment of endotoxin-induced ileus.
De Winter
Benedicte Y
BY
Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, Faculty of Medicine, University of Antwerp, Belgium. benedicte.dewinter@ua.ac.be
Bredenoord
Albert J
AJ
Van Nassauw
Luc
L
De Man
Joris G
JG
De Schepper
Heiko U
HU
Timmermans
Jean-Pierre
JP
Pelckmans
Paul A
PA
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology; D018738:Hexamethonium / Q000494:pharmacology; D045823:Ileus / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology*; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D008070:Lipopolysaccharides; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D010446:Peptide Fragments; D011719:Pyrazines; D011725:Pyridines; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C058636:calcitonin gene-related peptide (8-37); D018738:Hexamethonium; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin