# Genetic dissection of visceral pain pathways

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $445,183

## Abstract

Abstract
The goal of this application is to explore therapeutic opportunities for visceral pain in a new set of cellular
targets within the spinal cord that will drive affective pain, rather than reflexive-defensive reactions. Pain from
deep tissues (e.g. visceral organs, joints, muscles and bones) is among the most prevalent and disruptive.
Major causes include inflammation, nerve injury and tumor growth. Translation of preclinical insight into the
neurobiology of pain towards new medications has been disappointing. In preliminary studies, my colleagues
and I have unmasked one of potential explanations for the lack of progress. Put briefly, in a series of studies on
cutaneous pain, we have identified a group of spinal ascending projection neurons, marked by Tac1-Cre, that
are essential for affective pain-indicative coping behaviors, but dispensable for first-line nocifensive-defensive
reactions. This disconnect at the level of cutaneous pain leads to a testable hypothesis. We propose that
affective and defensive elements of the response to noxious visceral stimuli could also be segregated at the
level of the spinal cord. Our study plan uses innovative genetic tools to probe testable predictions of this
hypothesis. We have two specific aims: Aim 1 is to test the prediction that unique spinal substrates are
associated with acute visceromotor reflexes versus affective visceral pain. This prediction is based on our
preliminary results, showing that two groups of spinal excitatory neurons (one is Tac1-Cre neurons), which are
activated by noxious colorectal distensions (CRD), send extensive ascending projections to distinct, though
partially overlapped sets of thalamic and midbrain nuclei. Meanwhile, we will test if a group of spinal inhibitory
neurons activated by CRD act to gate visceral motor reflexes and/or affective pain. Aim 2 is to test the
prediction that unique spinal substrates are associated with inflammatory visceral pain. Our pilot studies have
identified two groups of spinal excitatory neurons that are activated by CRD only after gastrointestinal (GI)
inflammation, and one of which (marked by VGLUT3-Cre) appears to be crucial for mediating sensitized
affective visceral pain. Together with three other groups of excitatory neurons that are already activated by
CRD under naïve conditions, we will determine if these five groups of neurons transmit sensitized visceromotor
reflexes, affective visceral pain, as well as the referred cutaneous pain induced by GI inflammation. All
together, these studies will provide new insight into spinal substrates mediating different dimensions of acute
and chronic visceral pain.

## Key facts

- **NIH application ID:** 9963272
- **Project number:** 5R01DK122833-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** QIUFU MA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,183
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963272

## Citation

> US National Institutes of Health, RePORTER application 9963272, Genetic dissection of visceral pain pathways (5R01DK122833-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963272. Licensed CC0.

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