# Serotonergic involvement in the interaction between alcohol and pain

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Chronic alcohol use is prevalent among the veteran population and can permanently alter brain function and
exacerbate existing health conditions. There is a growing literature that alcohol use may exacerbate chronic pain
and predispose to pain disorders, but the neural mechanisms are still unknown. Our preliminary data suggests
that mice exposed to chronic intermittent ethanol (CIE) exhibit increased pain sensitivity, hyperexcitability of
serotonin (5-HT) neurons, and elevated 5-HT immunoreactivity in the dorsal raphe nucleus (DRN). Ablation of
5-HT neurons in the DRN also reduced nociception in the Von Frey test, suggesting that hyperactivity in these
neurons following CIE may facilitate pain. DRN neurons project principally to the forebrain and have excitatory,
5-HT-mediated input to the paraventricular nucleus of the thalamus (PVT), which can also facilitate pain via
projections to the central amygdala (CeA). At the same time, CIE reduced tryptophan-hydroxylase 2 (Tph2)
expression in the raphe magnus (RMg), which is another serotonergic nucleus that projects to the dorsal horn
(DH) of the spinal cord and may promote anti-nociception.
The overarching goal of this application is to investigate two discrete serotonergic mechanisms of alcohol-
induced hyperalgesia. We propose that CIE increases activity in the 5-HT DRN→PVT pathway that facilities
pain and decreases activity in the 5HT RMg→DH pathway that inhibits pain. In Aim 1, we will examine the
effects of CIE on activity in 5-HT DRN→PVT projection neurons using in vivo fiber photometry and ex vivo slice
electrophysiology as complementary approaches. We will then examine 5-HT release dynamics in the PVT with
fiber photometry, followed by slice electrophysiology to dissect the effect of this enhanced 5-HT release on neural
activity in PVT→CeA neurons. We will then determine whether CIE can alter 5-HT receptor expression in
PVT→CeA projection neurons using translating ribosome affinity purification (TRAP) and RT-PCR. These
experiments will reveal whether CIE can promote 5-HT signaling in the PVT and activate PVT projections to the
CeA that facilitate pain. Aim 2 will investigate the effects of CIE on 5-HT RMg neurons using similar approaches
as in Aim 1. We will also examine pain-evoked activity in DH neurons receiving input from 5-HT RMg neurons
using fos immunohistochemistry. 5-HT receptor gene expression in DH neurons receiving input from the RMg
will also be examined using a combination of TRAP and RT-PCR. Finally in Aim 3, we will evaluate the respective
contributions of the 5-HT DRN→ PVT and 5-HT RMg→DH pathways to pain and alcohol-induced hyperalgesia
using multiplexed DREADDS that enable simultaneous manipulation of both pathways in the same animals.
Together, these experiments will generate mechanistic insight into the role of chronic alcohol abuse in
predisposing to and precipitating pain disorders.

## Key facts

- **NIH application ID:** 10803226
- **Project number:** 1I01BX005778-01A1
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Catherine Anne Marcinkiewcz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803226

## Citation

> US National Institutes of Health, RePORTER application 10803226, Serotonergic involvement in the interaction between alcohol and pain (1I01BX005778-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10803226. Licensed CC0.

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