# Investigation of non-canonical opioid signaling in the prefrontal cortex of alcohol-dependent rats

> **NIH NIH R21** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $188,813

## Abstract

Project Abstract
Current treatments of Alcohol Use Disorder (AUD) have shown moderate success in reducing heavy alcohol
drinking but are marred with the problem of treatment adherence. In the clinic, opiate receptor pharmaceutics
are often combined with cognitive behavioral therapies to improve long-term abstinence. These findings suggest
an important relation between endogenous opioid signaling and cognitive factors in the treatment of AUD;
however, lapses in treatment can quickly reinstate alcohol drinking, highlighting a knowledge gap in our
understanding of how these mechanisms may influence long-term misuse. In this regard, alcohol consumption
stimulates the release of endogenous opioids, including enkephalins that bind to mu-type opioid receptors (MOR)
commonly found in limbic areas of the brain. The manipulation of MOR signaling alters the rewarding properties
of alcohol, with agonists facilitating reward and consumption, and antagonists blocking these responses. The
shared relation between opioidergic responses that underlie motivation and cognition are not well understood
but present a focal point for addressing complex pathologies that may underlie alcohol-related sensitivities. In
this regard, MORs are found in frontal cortical regions that modulate cognitive function, such as the medial
prefrontal cortex (mPFC). Preclinical studies in our laboratory demonstrate that alcohol dependence in rats
decreases the phosphorylation of MOR in the mPFC, and increases expression of the neuropeptide precursor,
proenkephalin (PENK). This pattern of changes overlaps with clinical observations of MOR desensitization in
AUD patients. The findings suggest that dependence may dysregulate opioidergic signaling in the mPFC,
although the extent to which such conditions surmise changes in the endogenous ligands is unclear. A better
understanding is warranted given that adherence to opiate antagonists diminishes over protracted abstinence
and may be undermined by molecular intermediates in the processing of small-opioid peptides. Here, we will
explore the central hypothesis that non-canonical PENK signaling in the mPFC plays a pivotal role in
dysregulating cognitive function during abstinence. Towards this goal, discovery-based and quantitative mass
spectrometry approaches will be combined with in vivo microdialysis to broadly capture PENK-mediated
signaling in alcohol-dependent rats undergoing abstinence (Aim 1). We will then explore the functional relevance
of non-canonical PENK signaling in an operant model of cognitive flexibility, and further determine whether
similar dysfunctions in dependence are modulated by mPFC MOR (Aim 2). The results are expected to provide
insight into druggable targets that extend beyond conventional opioidergic signaling processes and will lay the
foundation for mechanistic studies exploring the role of non-canonical PENK signaling in driving vulnerability to
addiction behavior.

## Key facts

- **NIH application ID:** 10936536
- **Project number:** 5R21AA030862-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** LUIS ALBERTO NATIVIDAD
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,813
- **Award type:** 5
- **Project period:** 2023-09-26 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936536

## Citation

> US National Institutes of Health, RePORTER application 10936536, Investigation of non-canonical opioid signaling in the prefrontal cortex of alcohol-dependent rats (5R21AA030862-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10936536. Licensed CC0.

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