# Neural Immune mechanisms of heroin withdrawal and stress

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $233,250

## Abstract

Project Summary/Abstract
Opiate withdrawal and post-traumatic stress disorder (PTSD) frequently present together in clinical settings.
Clinical data also suggests that opiate abuse is a potential risk factor for PTSD. Understanding the mechanism
for co-occurrence and vulnerability to PTSD in opiate users will provide information about the consequences of
opiate abuse and inform the development of interventions that mitigate both the symptoms of heroin withdrawal,
a known risk factor for relapse, and heroin’s long-term effects on stress disorders. Our laboratory has identified
the hippocampal mechanisms required for development of stress enhanced fear learning (SEFL), an animal
model of PTSD. We established that the severe stressor in the SEFL paradigm induces dorsal hippocampal (DH)
interleukin-1β (IL-1β) in astrocytes, and that directly blocking DH IL-1 signaling with IL-1 receptor antagonist (IL-
1RA) after severe stress prevents subsequent enhanced fear learning. We have developed a pre-clinical model
to investigate the effect of heroin withdrawal on enhanced fear learning. We found that withdrawal from escalating
heroin administration substitutes for a severe stressor in the SEFL paradigm and that heroin withdrawal similarly
increases DH IL-1β and GFAP expression, a marker of astrocyte activation. Accordingly, the plan is to test the
innovative unique hypothesis that heroin withdrawal also acts through hippocampal IL-1β and alterations in
astrocytes that result in enhanced fear learning. Specific Aim 1 will test the hypothesis that heroin withdrawal-
induced enhancement of fear learning is mediated by IL-1β in the DH. Specifically, we will determine (A) whether
withdrawal-induced enhanced fear learning is associated with potentiation of IL-1β signaling specifically in
astrocytes, (B) whether blockade of DH IL-1 receptors with IL-1RA during withdrawal will protect against the
development of enhanced fear learning following heroin withdrawal, (C) whether DH infusion of exogenous IL-
1β will substitute for the effects of stress and/or withdrawal to induce enhanced fear learning, and (D) whether
pharmacological blockade of DH IL-1 receptors during heroin withdrawal will prevent withdrawal symptoms.
Predicted results are that heroin withdrawal will increase IL-1β levels, primarily in astrocytes, and that the effect
of heroin withdrawal on enhanced fear learning will be blocked by IL-1RA and mimicked by infusion of IL-1β in
the DH. Also, the symptoms of withdrawal will be attenuated or blocked by the administration of IL-1RA.
Collectively, the results elucidate the critical role of DH IL-1 signaling in heroin withdrawal and enhanced fear
learning. Specific Aim 2 will use advanced 3-D reconstruction of individual cells to conduct morphometric analysis
in combination with assessment of synaptic markers (postsynaptic density 95 and Synapsin 1) to test innovative
hypotheses that changes in the morphometric properties of astrocytes, and/or alterations o...

## Key facts

- **NIH application ID:** 9894947
- **Project number:** 1R21DA048241-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** DONALD T LYSLE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894947

## Citation

> US National Institutes of Health, RePORTER application 9894947, Neural Immune mechanisms of heroin withdrawal and stress (1R21DA048241-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894947. Licensed CC0.

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