# Microglia and Epigenetic Regulation in Opioid Addiction

> **NIH NIH DP1** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $460,500

## Abstract

PROJECT SUMMARY
 Drug addiction is a chronic, relapsing disease characterized by compulsive drug seeking and
use, despite harmful consequences. More specifically, opioid use disorder (OUD), often stemming from
the misuse of prescription opioid painkillers, represents an urgent social and health crisis, responsible
for approximately 50,000 yearly overdose deaths and incurring an annual burden of $78.5B in medical
treatment, lost productivity and legal costs in the US (See NIDA website). While effective treatments
exist for opioid overdose events, the lack of effective therapeutics for long-term abstinence and
prevention of relapse highlight the pressing need for alternative approaches to study OUD.
 Moving beyond their direct effect on neuronal function, opioids are also known to act directly on
microglia. Microglia are resident immune cells in the brain that serve as key drivers of
neuroinflammation, a physiological process aimed at restoring homeostasis typically in response to a
traumatic, chemical or ischemic insult to the central nervous system. A hallmark of neuroinflammation
is microglial activation, and the transcriptional mechanisms underlying microglial activation operate
under control of epigenetic remodeling of histone proteins. In the context of OUD, it has been previously
shown that opioids can induce activation of microglia and that reduction in neuroinflammation can curb
craving for opioid painkillers.
 Considering the known role of epigenetics in addiction and the emerging role of microglia in this
disease, we propose to investigate the epigenetic underpinnings of microglial activation in OUD. More
specifically, we will focus on the changes in histone lysine methylation in microglia of the brain reward
system and how these changes comport with transcriptional programs across various phases of opioid-
taking (maintenance, early withdrawal, and craving) by using a mouse model of intravenous
remifentanil self-administration (IVSA). Furthermore, we will explore the role of this epigenetic
modification in regulating opioid-induced microglial activation, opioid-seeking and relapse by
pharmacological and genetic manipulation of Kdm6b, a histone lysine demethylase enriched in
microglia. In conclusion, results from these experiments have the potential to not just broaden our
understanding of the epigenetic mechanisms underlying OUD, but rather push the field of addiction
epigenetics beyond the neuron and into cell types that could yield exciting new therapeutic avenues for
the treatment this devastating disease.

## Key facts

- **NIH application ID:** 10051132
- **Project number:** 1DP1DA051828-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Luis Miguel Tuesta
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,500
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051132

## Citation

> US National Institutes of Health, RePORTER application 10051132, Microglia and Epigenetic Regulation in Opioid Addiction (1DP1DA051828-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10051132. Licensed CC0.

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