# Chronic Stress and Visceral Pain Heterogeneity: Role of Endocannabinoid & Epigenetic Regulatory Pathways

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $195,000

## Abstract

Project Summary
Chronic stress is associated with enhanced abdominal pain (visceral hyperalgesia) in animal models and the
human. Both animal models and humans demonstrate significant heterogeneity in their perception of pain in
response to chronic stress, e.g. some individuals have a modest enhancement and others a marked
enhancement in their perception of pain. The mechanistic basis for this diverse pain response to stress is
unknown but represents one of the fundamentally important unanswered questions in basic and clinical pain
research. Several hypotheses have been proposed to explain chronic stress-induced visceral hyperalgesia
including sensitization of central and peripheral pain pathways and, recently, we reported that the magnitude of
visceral pain response correlates with the magnitude of increased intestinal epithelial paracellular permeability
linked to down-regulation of epithelial tight junction protein expression in the rat colon. Emerging evidence
implicates a potentially pivotal role for epigenetic and endocannabinoid pathways in regulating pain perception.
It is unknown whether epigenetic regulatory pathways play a role in chronic stress-induced increase in
intestinal permeability and concomitant visceral hyperalgesia. We propose the novel hypothesis that the
heterogeneous visceral pain response to chronic stress will be linked to distinct profiles of DNA
methyltransferases (Dnmts) and histone tail modification enzymes observed in control rats that regulate
intestinal epithelial tight junction protein expression, which will predict the magnitude of visceral hyperalgesia
response to chronic stress. Specific Aim 1 will profile the visceral pain response to colorectal distention, colon
permeability and epithelial tight junction protein expression in male Wistar rats before and after ten days of
chronic, intermittent water avoidance stress. Each animal will serve as its own control. Specific Aim 2 will
elucidate the epigenetic and endocannabinoid regulatory pathways that underlie the differential pain response
to chronic stress including differential down-regulation of colon epithelial tight junction proteins, differential
increase in paracellular permeability and higher visceral pain response in a subpopulation of male Wistar rats.
To assess translatability of the animal results to the human, we will perform complementary studies using
human colonoids derived from controls and age-matched patients with diarrhea-prone Irritable Bowel
Syndrome (IBS-D) and differentiated Caco-2 cells exposed to stress levels of cortisol to measure permeability,
tight junction protein expression and relevant epigenetic regulatory pathways before and after cortisol
treatment. These studies will generate essential data for a subsequent R01 application to explore the
mechanistic basis for the heterogeneous pain response to stress.

## Key facts

- **NIH application ID:** 9929047
- **Project number:** 5R21NS113127-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SHUANGSONG HONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2019-05-15 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929047

## Citation

> US National Institutes of Health, RePORTER application 9929047, Chronic Stress and Visceral Pain Heterogeneity: Role of Endocannabinoid & Epigenetic Regulatory Pathways (5R21NS113127-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929047. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*