# Epigenomic labeling of cells that drive drug abuse behavior

> **NIH NIH DP1** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $537,000

## Abstract

PROJECT SUMMARY
In an effort to provide pain relief to tens of millions of patients with chronic pain, opioids are one of the most
commonly prescribed medications in the United States. Large segments of the population are thus exposed to
the detrimental side effects of opioids, which can be life threatening and include addiction and respiratory failure.
Compulsive opioid use despite these negative consequences defines opioid use disorder, a condition that is
responsible for nearly 50,000 deaths and $80 billion in medical costs annually. Thus, there is an urgent need for
the development of improved treatments for opioid use disorder.
One of the greatest challenges in treating opioid use disorder is its chronic nature with patients often relapsing
after long periods of drug abstinence. Persistent epigenomic changes in the nucleus accumbens of patients with
opioid use disorder are thought to contribute to its chronic, relapsing course. It has remained challenging,
however, to translate this knowledge into novel therapeutic approaches because it has not been possible to
selectively target the epigenomically-modified neurons involved in drug-seeking behavior without also affecting
nearby cells in unrelated circuits.
Here we present an innovative approach to label cells that drive opioid-seeking behavior based on their unique
epigenomic profile. To do this, we will first map at single-cell resolution, the regions of chromatin that are
selectively accessible in mouse nucleus accumbens neurons after morphine self-administration, an established
model of opioid use disorder. Some of these genomic regions will act as functional gene regulatory elements
that activate gene expression (e.g. gene enhancers) after morphine self-administration. To identify these
functional gene enhancers, we will generate an adeno-associated viral library in which each putative element
promotes the expression of a unique barcode. We will then use single-nucleus RNA-sequencing to rapidly screen
this viral library in vivo for the elements that selectively drive expression of their barcode in the nucleus
accumbens neurons that have been epigenomically altered by morphine self-administration. The most selective
viral candidate will be used to express inhibitory chemogenetic channels for controlling morphine-seeking
behavior.
Successful completion of this proposal will establish a fundamentally new approach to selectively label, purify,
and control cells that drive opioid-seeking behavior. This approach offers a number of advantages over current
state-of-the-art technologies including the ability to label cells involved in drug-seeking behavior without need for
transgenic mice or precisely timed conditioned stimuli. By using evolutionarily-conserved gene regulatory
elements to drive viral expression, this approach also has the potential to translate to patients with refractory
opioid use disorder.

## Key facts

- **NIH application ID:** 10293229
- **Project number:** 1DP1DA054343-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** William Russell Renthal
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $537,000
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293229

## Citation

> US National Institutes of Health, RePORTER application 10293229, Epigenomic labeling of cells that drive drug abuse behavior (1DP1DA054343-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10293229. Licensed CC0.

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