# Noradrenergic Plasticity in Opioid Withdrawal

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $425,845

## Abstract

PROJECT SUMMARY
The opioid epidemic in the United States is profound, with an annual economic burden of $95.8 billion dollars
(2016 dollars) and a total cost of over $1Trillion since 2001. Moreover, drug overdose is now the no. 1 cause of
accidental death with over 72,000 lives lost in 2017, and opioid overdoses account for over 60% of these deaths.
In order to develop pharmacological and behavioral therapies to treat opioid use disorder (OUD), it is important
to understand the neural circuitry and neuroadaptation that occurs following opioid use and withdrawal. Disorders
on the affective spectrum often exhibit high comorbidity. Therefore, it is imperative to understand how opioids
alter critical circuits and neurotransmitters that regulate addiction-like behaviors, aversion/anxiety and the
response to stress. A node in the extended amygdala, the bed nucleus of the stria terminalis (BNST), receives
the densest innervation of norepinephrine (NE, a stress responsive neurotransmitter) in the brain. The BNST is
a major contributor to opioid withdrawal behaviors and previously, we demonstrated that morphine exposure and
withdrawal modulates BNST NE release and uptake mechanisms in rats. Our preliminary data demonstrate that
chronic stress enhances the same noradrenergic circuitry mice, and that opioid exposure and withdrawal
modulates NE neurons. Furthermore, in mice we observe sex specific acute withdrawal behaviors, withdrawal
induced disruption of sleep rhythms, and anxiety-like behavior in protracted abstinence. The BNST is a sexually
dimorphic brain region, and we observe further sex differences in (and some similarities) in BNST physiology.
Intriguingly, our data suggest that there may be reductions in excitatory transmission in select circuitry following
opioid withdrawal, which may ultimately alter BNST output to classical reward circuits. These data inform the
central hypothesis of our proposal investigated in 3 aims: opioid withdrawal 1. enhances the synaptic drive onto
NE neurons innervating the BNST, 2. facilitates enhanced noradrenergic transmission within the BNST, and 3.
induces glutamatergic plasticity within the BNST intensifying opioid withdrawal syndrome related behaviors.

## Key facts

- **NIH application ID:** 9973280
- **Project number:** 1R01DA049261-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Zoe Anastasia McElligott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,845
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973280

## Citation

> US National Institutes of Health, RePORTER application 9973280, Noradrenergic Plasticity in Opioid Withdrawal (1R01DA049261-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973280. Licensed CC0.

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