Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum.

Journal Article (Journal Article)

BACKGROUND & AIMS: Nerves have been suggested to mediate the effects of bacterial toxins in intestinal diseases. However, the mechanisms involved are unknown. This study examined endogenous substance P (SP) activation of the substance P receptor (SPR) on enteric neurons in the rat ileum after exposure to intraluminal Clostridium difficile toxin A. METHODS: After intraluminal injection of toxin A in ileal loops, tissue was examined for pathological changes by histology and for SPR activation by immunocytochemical analysis of SP-induced SPR endocytosis. RESULTS: After toxin A administration, > 70% of enteric neurons showed SPR endocytosis and became swollen with thickened dendrites. In contrast, SPRs in control rats were largely confined to the plasma membrane. Rats denervated of primary afferent fibers with neonatal capsaicin injection and animals pretreated with a nonpeptide SPR antagonist showed few endosomal SPRs, and the pathological inflammatory effects of toxin A were ablated. CONCLUSIONS: Intraluminal toxin A causes the release of SP from primary afferent neurons: this endogenous SP then acts on enteric neurons in the submucosal and myenteric plexuses. SP is the primary mediator of an axon reflex mediating neurogenic inflammation in the intestine. SPR blockade may prove to be a novel therapy used to prevent intestinal inflammation.

Full Text

Duke Authors

Cited Authors

  • Mantyh, CR; Pappas, TN; Lapp, JA; Washington, MK; Neville, LM; Ghilardi, JR; Rogers, SD; Mantyh, PW; Vigna, SR

Published Date

  • November 1996

Published In

Volume / Issue

  • 111 / 5

Start / End Page

  • 1272 - 1280

PubMed ID

  • 8898641

International Standard Serial Number (ISSN)

  • 0016-5085

Digital Object Identifier (DOI)

  • 10.1053/gast.1996.v111.pm8898641


  • eng

Conference Location

  • United States