# Cellular mechanisms of antidepressant drug actions in neuropathic pain models

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $530,497

## Abstract

This project aims to elucidate epigenetic and transcriptional mechanisms in the reward brain circuitry which
mediate long-term pain states and responses to antidepressant medications.
Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the
drugs used to treat the pain-like symptoms of this disorder demonstrate low efficacy and major side-effects. And,
well documented among classes of opioids many of the current treatments can lead to debilitating addiction.
There is a pressing need for the development of more efficacious and better tolerated medications for chronic
neuropathic pain. Tricyclic antidepressants (TCAs) and the selective, serotonin/norepinephrine reuptake
inhibitors (SNRIs) contain both antiallodynic and antidepressant properties; however, they demonstrate slow
onset of action and longtime usage often is accompanied by severe adverse effects. Understanding the
intracellular mechanisms mediating the actions of TCAs and SNRIs will help the development of novel and more
efficacious medications for the treatment of neuropathic pain. Our earlier findings identified a key role of the
epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of TCAs/SNRIs in models
of neuropathic pain. HDAC5 in the Nucleus Accumbens (NAc) binds to chromatin complexes to suppress the
expression of several genes that affect synaptic function, including the transcription factor MEF2C. Our recent
preliminary findings suggest that promotion of MEF2C activity in the NAc leads to recovery from neuropathic pain
states. Moving forward, we propose to use genetic mouse models, biochemical and genomic approaches to
understand the impact of chronic pain in the nuclear activity of HDAC5, and the NAc circuits associated with
HDAC5 actions. Furthermore, we will test known HDAC5 target genes, such as MEF2C, for their ability to
promote recovery from chronic pain states and enhance the efficacy of antidepressants. We will employ genomic
approaches to identify additional HDAC5 targets and test for their role in chronic pain and SNRI efficacy. Our
findings will help to provide insights regarding epigenetic and transcriptional mechanisms that control the
maintenance of chronic pain and responsiveness to pain-alleviating drugs.

## Key facts

- **NIH application ID:** 9952434
- **Project number:** 5R01NS086444-07
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Venetia Zachariou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,497
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952434

## Citation

> US National Institutes of Health, RePORTER application 9952434, Cellular mechanisms of antidepressant drug actions in neuropathic pain models (5R01NS086444-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952434. Licensed CC0.

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