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

C. R. Mantyh, T. N. Pappas, J. A. Lapp, M. K. Washington, L. M. Neville, J. R. Ghilardi, S. D. Rogers, Patrick W Mantyh, S. R. Vigna

Research output: Contribution to journalArticle

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Abstract

Background and 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.

Original languageEnglish (US)
Pages (from-to)1272-1280
Number of pages9
JournalGastroenterology
Volume111
Issue number5
DOIs
StatePublished - 1996
Externally publishedYes

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Neurokinin-1 Receptors
Substance P
Ileum
Neurons
Endocytosis
Neurokinin-1 Receptor Antagonists
Submucous Plexus
Neurogenic Inflammation
Activation Analysis
Bacterial Toxins
Afferent Neurons
Myenteric Plexus
Intestinal Diseases
Injections
Capsaicin
Dendrites
Intestines
Axons
Reflex
Histology

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Mantyh, C. R., Pappas, T. N., Lapp, J. A., Washington, M. K., Neville, L. M., Ghilardi, J. R., ... Vigna, S. R. (1996). Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. Gastroenterology, 111(5), 1272-1280. https://doi.org/10.1053/gast.1996.v111.pm8898641

Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. / Mantyh, C. R.; Pappas, T. N.; Lapp, J. A.; Washington, M. K.; Neville, L. M.; Ghilardi, J. R.; Rogers, S. D.; Mantyh, Patrick W; Vigna, S. R.

In: Gastroenterology, Vol. 111, No. 5, 1996, p. 1272-1280.

Research output: Contribution to journalArticle

Mantyh, CR, Pappas, TN, Lapp, JA, Washington, MK, Neville, LM, Ghilardi, JR, Rogers, SD, Mantyh, PW & Vigna, SR 1996, 'Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum', Gastroenterology, vol. 111, no. 5, pp. 1272-1280. https://doi.org/10.1053/gast.1996.v111.pm8898641
Mantyh, C. R. ; Pappas, T. N. ; Lapp, J. A. ; Washington, M. K. ; Neville, L. M. ; Ghilardi, J. R. ; Rogers, S. D. ; Mantyh, Patrick W ; Vigna, S. R. / Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. In: Gastroenterology. 1996 ; Vol. 111, No. 5. pp. 1272-1280.
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abstract = "Background and 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.",
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AU - Pappas, T. N.

AU - Lapp, J. A.

AU - Washington, M. K.

AU - Neville, L. M.

AU - Ghilardi, J. R.

AU - Rogers, S. D.

AU - Mantyh, Patrick W

AU - Vigna, S. R.

PY - 1996

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