# Mechanisms of Epigenetic Plasticity in Neuropathic Pain

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $447,830

## Abstract

Mechanisms of Epigenetic Plasticity in Neuropathic Pain
The major objective of our project is to determine how traumatic nerve injury impacts epigenetic regulatory
networks involved in chronic pain. Neuropathic pain remains a major clinical problem and therapeutic challenge.
Both sustained changes in gene expression in primary afferent neurons and synaptic plasticity at the spinal cord
level are essential for to the development of chronic pain. α2δ-1 (encoded by the Cacna2d1 gene) is a
clinically validated neuropathic pain target and mediates the therapeutic actions of gabapentinoids.
Traumatic nerve injury and certain cancer chemotherapeutic drugs cause α2δ-1 upregulation in the dorsal root
ganglion and spinal cord, which augments nociceptive input to spinal dorsal horn neurons by directly interacting
with NMDA receptors. Yet we know almost nothing about how nerve injury initiates and sustains the high
expression level of α2δ-1. Acetylation of lysine residues in histone tails is dynamically regulated by various
histone deacetylases (HDACs). However, the specific HDAC subtypes responsible for the upregulation of α2δ-
1 and other neuroplasticity-related genes in neuropathic pain have not been rigorously studied or identified. To
address this key knowledge gap, we will specifically determine the role of class I HDAC subtypes in the control
of histone acetylation and expression of α2δ-1 and other gene targets implicated in synaptic plasticity in two
neuropathic pain models. On the basis of our preliminary data, we propose to test the overall hypothesis that
nerve injury and chemotherapy diminish HDAC2 occupancy to induce histone hyperacetylation, via CK2-
mediated phosphorylation, at the promoters of Cacna2d1 and other neuroplasticity-related genes in the DRG
and that HDAC2 constitutively restrains chronic pain by repressing Cacna2d1 transcription and α2δ-1–
dependent NMDA receptor activation at the spinal cord level. We will apply several innovative and vigorous
approaches, including unbiased genome-wide epigenetic analyses, transgenic mice, and synaptic recordings to
study neuroplasticity at molecular, cellular, and behavioral levels. Our project will generate fundamental new
information about the epigenetic basis of neuropathic pain. Findings from our project are expected to advance
our knowledge of molecular mechanisms of epigenetic plasticity and to guide the development of new strategies
for treating neuropathic pain.

## Key facts

- **NIH application ID:** 10802375
- **Project number:** 5R01NS132398-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shao-Rui Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,830
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802375

## Citation

> US National Institutes of Health, RePORTER application 10802375, Mechanisms of Epigenetic Plasticity in Neuropathic Pain (5R01NS132398-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10802375. Licensed CC0.

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