# Developing a Gene-Based Approach for Lasting Protection from Opioid Use Disorder

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

PROJECT SUMMARY
 Opioid use disorders pose a substantial public health burden, with consistently high rates of morbidity
and mortality. Though many interventions exist, all modalities suffer some degree of treatment nonadherence
and response failure, which suggests a need for more effective solutions. When bound to Gi-coupled Mu opioid
receptors (MuORs) in ventral tegmental area (VTA) GABAergic neurons, opioids cause disinhibition of VTA
dopaminergic neurons, which then increases dopamine release in the nucleus accumbens (NAc), a key driver
of reward signaling in the brain. Various methods of modulating VTA activity have been found to modify
opioid-seeking behavior, but little work has been done to take this information in a therapeutic direction.
Inspired by recent work using inhibitory DREADDs to attenuate heroin seeking behavior, this project seeks to
utilize the MuOR itself as a means to inhibit reward signaling in a way that has clear translational value.
 The MuOR mutation D114(2.50)N is one of the best characterized variants of this receptor, and is
known to exhibit a significant reduction in binding affinity and potency for various opioid ligands compared to
the wild-type receptor. This mutant, which will be referred to as LAMuOR (Low Affinity Mu Opioid Receptor),
may be exploited to create a genetically encoded tool that, when expressed in the VTA, inhibits the response of
the reward pathway to exogenously administered opioids, while remaining unresponsive to endogenous
ligands. Thus, the goal of this project is to test the hypothesis that LAMuOR suppresses opioid taking by
responding preferentially to opioids of abuse – such as during fentanyl self-administration – while remaining
unresponsive during physiological reward signaling. If successful, LAMuOR may ultimately prove to be a novel
translational strategy by which a single treatment could confer life-long protection from opioid use disorders.

## Key facts

- **NIH application ID:** 10846653
- **Project number:** 5F31DA053774-03
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Kelly Clemenza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2022-06-07 → 2025-06-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846653

## Citation

> US National Institutes of Health, RePORTER application 10846653, Developing a Gene-Based Approach for Lasting Protection from Opioid Use Disorder (5F31DA053774-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846653. Licensed CC0.

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