# The molecular mechanisms of astrocytes-neurons interaction in the morphine use disorder

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2024 · —

## Abstract

Opioid use disorder (OUD) has substantial negative consequences on veterans' mental and physical health,
work performance, housing status, and social function. Opioid drug abuse has reached an epidemic level in
the United States. There is an increased risk of overdose death with higher daily opioid doses for increasing
analgesic effect. The Veterans Health Administration (VHA) recognizes the clinical challenges to successfully
prescribing opioids safely for our veterans. Morphine withdrawal (MW) is one of determinants of opiate abuse
in OUD individuals, yet its mechanisms are poorly understood, and effective therapies are still lacking.
 MW activates astrocytes to release neuroinflammatory factors. Emerging evidence shows that
neuroinflammatory factor Lipocalin 2 (LCN2) from reactive astrocytes is associated with a variety of nervous
system injuries and neuroinflammation. Our preliminary data showed that spontaneous MW (S-MW) induced
TLR4, NF-kB (RelA/p65), and LCN2 from astrocytes. LCN2 receptor (LCN2-R) is located in the brainstem
periaqueductal gray (PAG) neurons in S-MW. Epigenetic writer EZH2 silences gene expression by generating
a methylated epigenetic mark at H3K27me3. Our preliminary data showed that S-MW increased neuronal
EZH2 and pCREB, and decreased anti-oxidative mitochondrial sirtuin 3 (Sirt3) in the PAG. The exact
molecular mechanisms of astrocytes to neuron activity in S-MW remain poorly understood. In the proposal,
we will test the hypothesis that glial activity induces the release of astrocytes-derived LCN2, which lowers
neuronal anti-oxidative Sirt3 and finally increases pCREB in the PAG in mice with S-MW. Specific Aim 1: To
determine whether astrocytic activation induces the overexpression of LCN2 through TLR4 and NF-κB in the
vlPAG in mice with S-MW. Specific Aim 2: To define whether LCN2-R mediates the lowered Sirt3 expression
leading to pCREB increases in the vlPAG neurons in mice with S-MW. A crucial feature of our work is the
ability to causally use new genetic/epigenetic and molecular assay, cell-type specific conditional knockout
(cKO) mice, cell type-selective viral-mediated gene transfer, and molecular-pharmacological approach. The
proposal will provide important insights into the pathogenesis of opioid withdrawal, and shed light on a novel
therapeutic target for opioid withdrawal of opioid withdrawal. The study will could lead, in the future, to the
development of new drugs for both the general population and veterans, based on our identification of the
mechanism of action of TLR4---LCN2---Sirt3---pCREB pathway during opioid withdrawal.

## Key facts

- **NIH application ID:** 10721350
- **Project number:** 5I01BX005114-02
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** SHUANGLIN HAO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721350

## Citation

> US National Institutes of Health, RePORTER application 10721350, The molecular mechanisms of astrocytes-neurons interaction in the morphine use disorder (5I01BX005114-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10721350. Licensed CC0.

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