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Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury

Gazzieri, D., Trevisani, M., Springer, J., Harrison, S., Cottrell, G. S., Andre, E., Nicoletti, P., Massi, D., Zecchi, S., Nosi, D., Santucci, M., Gerard, N. P., Lucattelli, M., Lungarella, G., Fischer, A., Grady, E. F., Bunnett, N. W. and Geppetti, P. (2007) Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury. Free Radical Biology and Medicine, 43 (4). pp. 581-589. ISSN 0891-5849

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To link to this item DOI: 10.1016/j.freeradbiomed.2007.05.018

Abstract/Summary

Although neurokinin 1 receptor antagonists prevent ethanol (EtOH)-induced gastric lesions, the mechanisms by which EtOH releases substance P (SP) and SP damages the mucosa are unknown. We hypothesized that EtOH activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to release SP, which stimulates epithelial neurokinin 1 receptors to generate damaging reactive oxygen species (ROS). SP release was assayed in the mouse stomach, ROS were detected using dichlorofluorescein diacetate, and neurokinin 1 receptors were localized by immunofluorescence. EtOH-induced SP release was prevented by TRPV1 antagonism. High dose EtOH caused lesions, and TRPV1 or neurokinin 1 receptor antagonism and neurokinin 1 receptor deletion inhibited lesion formation. Coadministration of low, innocuous doses of EtOH and SP caused lesions by a TRPV1-independent but neurokinin 1 receptor-dependent process. EtOH, capsaicin, and SP stimulated generation of ROS by superficial gastric epithelial cells expressing neurokinin 1 receptors by a neurokinin 1 receptor-dependent mechanism. ROS scavengers prevented lesions induced by a high EtOH dose or a low EtOH dose plus SP. Gastric lesions are caused by an initial detrimental effect of EtOH, which is damaging only if associated with TRPV1 activation, SP release from sensory nerves, stimulation of neurokinin 1 receptors on epithelial cells, and ROS generation.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30270
Uncontrolled Keywords:Animals Central Nervous System Depressants/toxicity Ethanol/*toxicity Fluorescent Antibody Technique Gastric Mucosa/*drug effects/metabolism/pathology Immunohistochemistry Male Mice Neurons/drug effects/*metabolism Rats Rats, Sprague-Dawley Reactive Oxygen Species/*metabolism Receptors, Neurokinin-1/drug effects/metabolism Reverse Transcriptase Polymerase Chain Reaction Substance P/drug effects/*secretion TRPV Cation Channels/*metabolism
Publisher:Elsevier

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