# Gut Mechanisms of Stress-Induced Comorbid Visceral Pain

> **NIH NIH F31** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $2,500

## Abstract

Project Summary/Abstract
Chronic comorbid pain or overlapping pain conditions (COPCs) can be devastating from both personal and
societal standpoints. Sufferers – predominantly women – present with two or more chronic pain disorders.
Etiology of COPCs is poorly understood but there is a strong link to emotional stress as a contributing factor.
We showed that in female rats with existing neuropathic trigeminal pain (CCI), 3-day forced swimming (FS)
stress induces lasting visceral hypersensitivity referred to the lower back. In rats with such comorbid visceral
pain, 5-HT3R protein expression is upregulated in the lumbosacral (L6-S1) spinal cord and corresponding
dorsal root ganglia (DRG). Consistently, intrathecal blockade of 5-HT3R transiently attenuates referred
hyperalgesia. These observations suggest the involvement of 5-HT3R-mediated sensitization of primary
afferents from the gut in stress-induced comorbid visceral pain. However, the underlying gut mechanisms
remain poorly understood. Accumulating recent evidence supports the importance of gut microbial
dysregulation in the pathogenesis of stress-induced visceral pain. But it is unclear whether stress-induced gut
dysbiosis mediates cellular and molecular mechanisms underlying the development of visceral pain. We
examined fecal microbiota composition of rats with neuropathic trigeminal pain before and after FS stress. Our
preliminary data show extensive compositional changes in the gut microbiome of female rats with referred
hyperalgesia. Furthermore, fecal microbiota transfer (FMT) from CCI+FS donors induces referred hyperalgesia
in CCI recipients with ongoing orofacial pain. This treatment does not much affect naïve recipients, which
underscores the importance of CCI-induced descending serotonergic facilitation. On the other hand, FMT from
naïve donors attenuates referred hyperalgesia in CCI+FS recipients. We hypothesize that CCI+FS induces gut
dysbiosis that contributes to dysregulation of 5-HT3R in the primary afferents from the gut. This dysregulation
is evident only at the protein level implicating a posttranscriptional mechanism, particularly microRNAs. Recent
literature supports the role of gut microbiota in regulating host microRNA expression. Therefore, we further
hypothesize that in CCI+FS rats, gut dysbiosis leads to reduced expression of 5-HT3R-targeting microRNAs in
primary afferents from the gut. This results in increased 5-HT3R protein expression without affecting its mRNA
levels. We will use multidisciplinary approaches to test our hypotheses as described in three aims. In aim 1, we
will examine the role of 5-HT3R in the pathogenesis of persistent referred low back pain. In aim 2, we will
address the role of gut microbial dysbiosis in the development of referred low back pain. In aim 3, we will
investigate gut microbiota-associated posttranscriptional mechanisms of altered 5-HT3R expression. Our study
is designed to tease out possible causality between peripheral gut mechanisms...

## Key facts

- **NIH application ID:** 10389174
- **Project number:** 3F31DE029420-02S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Jamila Asgar
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2021-04-16 → 2021-08-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389174

## Citation

> US National Institutes of Health, RePORTER application 10389174, Gut Mechanisms of Stress-Induced Comorbid Visceral Pain (3F31DE029420-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10389174. Licensed CC0.

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