# Serotonin and Pain Modulation

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $483,040

## Abstract

Project Summary/Abstract
Chronic pain is the most common complaint of patients. Most chronic pain patients are resistant to therapy, in
large part because the underlying pathophysiology of their chronic pain condition is unknown. The ultimate
goal of this research program is to fill this critical gap. Pain is strongly modulated by the rostroventral medulla
(RVM) that directly regulates the activity of nociceptive dorsal horn neurons. Prominent in RVM are serotonin-
containing neurons. However, the role of these neurons in chronic pain remains controversial, with evidence
for both pathological increases and decreases in 5HT output. Our exciting preliminary findings—using a model
of chronic pain after chronic constriction injury of the infraorbital nerve (CCI-Pain)—may resolve this
important controversy. We show that, in CCI-Pain, RVM-5HT neuronal activity is amplified, resulting in
abnormally high release of 5HT in the caudal dorsal horn – trigeminal nucleus (SpVc). This causes SpVc
neurons to produce a barrage of after-discharges (ADs) that far outlast nociceptive stimuli, and that are
considered a manifestation of chronic pain. The increased 5HT release also potentiates the strength of
nociceptive inputs to SpVc neurons. Coupled with our previous demonstration that reducing 5HT levels in
RVM suppresses ADs and blocks pain sensitization, we hypothesize that increased serotonergic drive from
RVM causes hyperexcitability of dorsal horn neurons, which results in chronic pain. Aim I tests the
hypothesis that amplified activity of 5HT-RVM neurons results in increased release of 5HT in SpVc and the
development of chronic pain. We test the prediction that the electrophysiological activity of optogenetically-
identified 5HT RVM –> SpVc projection neurons is amplified in CCI-Pain. We will also use in vivo fast
scanning voltammetry, and quantitative mass spectrometry, to test the prediction that CCI-Pain is associated
with increased 5HT release in SpVc. Aim II tests the hypothesis that increased 5HT release is causally related
to the development of chronic pain. We will test the prediction that in vivo optogenetic release of 5HT from
RVM terminals in SpVc results in signs of sensory and affective pain, and that these signs are exacerbated by
repeated 5HT release. We will also test the converse prediction, that optogenetic inhibition of these 5HT
terminals results in relief from CCI-Pain. Aim III tests the hypothesis that amplified 5HT activity produces
chronic pain by inducing abnormal ADs in dorsal horn neurons. We will test the prediction that in vivo
optogenetic release of 5HT induces ADs in SpVc neurons of uninjured animals, and that optogenetic inhibition
of 5HT release will suppress ADs in CCI-Pain animals. Aim IV tests the hypothesis that amplified 5HT activity
produces chronic pain by potentiating primary afferent inputs to dorsal horn neurons. We will test the
prediction that optogenetic release of 5HT in vitro evokes potentiation of trigeminal in...

## Key facts

- **NIH application ID:** 9937847
- **Project number:** 5R01NS104297-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ASAF KELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,040
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937847

## Citation

> US National Institutes of Health, RePORTER application 9937847, Serotonin and Pain Modulation (5R01NS104297-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937847. Licensed CC0.

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