Gastroenterology

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 524-534
Gastroenterology

Basic-alimentary tract
Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats

https://doi.org/10.1053/j.gastro.2004.05.019Get rights and content

Abstract

Background & Aims: Maternal deprivation (MD) increases nerve growth factor (NGF) expression and colonic mast cell density and alters visceral sensitivity. This study aimed to establish whether NGF overexpression induced by neonatal stress is involved in altered visceral sensitivity and gut mucosal integrity in adult rats. Methods: Male Wistar rat pups were either submitted to MD and treated with anti-NGF antibodies or left with their dam and treated daily with NGF. All rats were tested 10 weeks later for visceral sensitivity and 12 weeks later for gut permeability, myeloperoxidase activity, and mast cell numbers. Colonic NGF and NGF receptor expression were determined at 14 days and 12 weeks of age. To determine the involvement of colonic NGF overexpression and mast cell hyperplasia in visceral hyperalgesia induced by MD, neonatally deprived adult rats received anti-NGF antibodies or doxantrazole. Results: MD increased visceral sensitivity to rectal distention, gut permeability, colonic myeloperoxidase activity, and mast cell density, and anti-NGF antibodies abolished these effects. Neonatal daily treatment with NGF mimicked the alterations induced by MD on both rectal sensitivity and mucosal barrier. In deprived compared with nondeprived rats, colonic NGF immunostaining and NGF messenger RNA were increased at 14 days and 12 weeks. Overexpression of NGF receptor messenger RNA, present at 14 days, was not observed later. Moreover, adult deprived rats treated with doxantrazole or anti-NGF antibodies exhibited normal gut permeability and visceral sensitivity to rectal distention. Conclusions: These data indicate that NGF triggers and maintains long-term alterations of visceral sensitivity and gut mucosal integrity induced by MD.

Section snippets

Animals

Primiparous pregnant female Wistar rats were individually housed in standard polypropylene cages containing 2.5 cm of wood chip bedding material. Rats were kept in a constant-temperature room (23°C ± 1°C) and maintained on a 12-hour light/dark cycle (lights on at 7 am). Food (UAR pellets; Epinay, France) and water were available ad libitum. Mothers and their pups, as well as the young rats after weaning on day 22, were kept in the same conditions.

MD

MD was performed according to a previously

Visceral sensitivity to RD

Gradual RD increased the frequency of abdominal contractions in a distention volume-dependent manner. In nondeprived rats, a volume of 0.8 mL was the threshold at which RD significantly increased (P < 0.05) the number of abdominal contractions compared with the predistention period. In deprived rats that received no injection, this threshold was significantly reduced (P < 0.05) to 0.4 mL (Figure 1).

Compared with nondeprived controls, neonatal MD significantly increased (P < 0.05) the number of

Discussion

This study provides new evidence that NGF plays a major role in triggering (neonatal period) and maintaining long-term visceral hyperalgesia and alteration of the colonic epithelial barrier in neonatally stressed rats by MD. We also show that mast cell degranulation participates in the mucosal and sensitivity alterations induced by neonatal MD. The first part related to the role of NGF in neonatal stress is supported by our data showing that the effects of neonatal separation are suppressed by

Acknowledgements

The authors thank Bernard Joseph for technical assistance.

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    Supported by the Institut National de la Recherche Agronomique (Paris, France).

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