# Cross-talk between the colon epithelium, colon afferents and sympathetic neurons regulate pain in the normal and inflamed colon

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $453,099

## Abstract

SUMMARY
Visceral pain is notoriously difficult to treat, often persisting long after the precipitating injury/disease is no
longer evident. In this application we will explore a novel, multicellular peripheral circuit that we hypothesize
explains many of the intractable features of chronic, visceral pain.
We now know that epithelial-neuronal communication is widespread, with numerous epithelial cell types
releasing neuroactive substances (e.g., ATP, ACh, 5HT, glutamate). This is particularly apparent in the colon
where we have found that channelrhodopsin (ChR2) -induced activation of colon epithelial cells produces high
frequency bursting of colon extrinsic primary afferent neurons (ExPAN’s), phenocopying physiologic stimuli and
inducing robust behavioral responses (visceromotor responses (VMR), a validated assay of hypersensitivity).
Building on these findings, new surprising data indicate colon epithelium also receives functional input from
sympathetic neurons; activation of sympathetic projections to the colon induces large, phase-locked calcium
signals in the epithelium. Closing the loop, we found that activation of ExPAN’s via colorectal distension (CRD)
induces calcium signals in the post-ganglionic sympathetic neurons projecting to the colon, and that ChR2-
induced activation of ExPAN’s induces cFos expression in these same neurons. That this multicellular circuit
plays a role in visceral pain is supported further by preliminary data that shows that inflammation (acute and/or
chronic) is correlated with increased signaling in all portions of this circuit.
Thus, the goal of the proposed experiments is to test the hypothesis that persistent visceral
hypersensitivity is due, at least in part, to amplification in an epithelial-ExPAN-sympathetic circuit such
that it is possible to treat pain by breaking any limb of this feed-forward circuit (Fig.1). This hypothesis
will be tested in 3 aims: Aim 1: Determine if persistent hypersensitivity induced in a model of IBD (DSS
(dextran sulfate sodium)) is due to increased epithelial signaling and/or ExPAN excitability, Aim 2: Determine if
DSS-induced inflammation increases the ability of ExPANs to activate sympathetic neurons in prevertebral
sympathetic ganglion (PrSG) directly (via synapses in PrSG) or indirectly (via a spinal cord circuit) and, Aim 3
Determine the ability of sympathetic neurons to drive activity in epithelial cells in naïve mice and in the DSS
model of IBD.

## Key facts

- **NIH application ID:** 9995064
- **Project number:** 1R01DK124955-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kathryn Marie Albers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,099
- **Award type:** 1
- **Project period:** 2020-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995064

## Citation

> US National Institutes of Health, RePORTER application 9995064, Cross-talk between the colon epithelium, colon afferents and sympathetic neurons regulate pain in the normal and inflamed colon (1R01DK124955-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995064. Licensed CC0.

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