# Corticotropin-releasing hormone receptor-1 antagonist attenuates visceral hypersensitivity induced by trinitrobenzene sulfonic acid colitis and maternal separation in rats

## TL;DR

This study shows that early life stress and past gut inflammation can cause long-term gut pain sensitivity in rats, which can be reduced by blocking a specific stress-related receptor.

## Contribution

The study demonstrates that CRH-R1 antagonism can reduce visceral hypersensitivity caused by maternal separation and colitis in rats.

## Key findings

- MS + TNBS rats showed increased visceral perception compared to controls.
- CP-154,526 significantly reduced the visceromotor response to colorectal distention in MS + TNBS rats.
- CRH-R1 pathway appears to mediate visceral hypersensitivity from early life stress and colitis.

## Abstract

The prevailing paradigm for the etiology of irritable bowel syndrome is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. In this study, we tested the hypotheses that (1) the combination of maternal separation (MS) and previous colorectal inflammation induces extensive visceral hypersensitivity in rats and (2) visceral hypersensitivity induced by maternal separation and previous colorectal inflammation in rats is mediated via the corticotropin-releasing hormone receptor-1 (CRH-R1) pathway.

Male rat pups were separated from their dams from postnatal day 2 to postnatal day 21. Acute colitis was induced by colorectal administration of trinitrobenzene sulfonic acid (TNBS) or vehicle on postnatal day 8. On postnatal day 50, the visceromotor response was evaluated by electromyography of the abdominal muscle in response to graded (10–80 mmHg) and phasic colorectal distention (CRD) one time. The same experiments were repeated after administration of the selective CRH-R1 antagonist CP-154,526 (20 mg/kg) or vehicle at 45 min before CRD.

Compared with control rats, visceral perception was increased in MS + TNBS rats. MS + TNBS rats showed a significantly larger visceromotor response to phasic CRD with 40 mmHg, 60 mmHg, and 80 mmHg. Compared with vehicle administration in MS + TNBS rats, administration of CP-154,526 significantly attenuated this visceromotor response to CRD with 40 mmHg, 60 mmHg, and 80 mmHg.

These findings suggest that the combination of previous colitis and early life stress induce visceral hypersensitivity, and that the CRH-R1 pathway may play a role in this sensitization.

The online version contains supplementary material available at 10.1186/s13030-025-00324-0.