# Neural basis of opioid-induced respiratory depression

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $337,515

## Abstract

Death from opioid overdose is primarily due to respiratory depression, yet little is known of the cellular
mechanisms of opioids on respiratory-controlling neurons. Breathing is controlled by a highly interconnected
network of neurons in the brainstem. Opioid-induced respiratory depression is due to activation of mu opioid
receptors located throughout in the brainstem respiratory network, including the Kölliker-Fuse (KF) in the
pons and respiratory control areas in the medulla. There are conflicting results regarding the importance of
these areas in opioid-induced respiratory depression. Based on preliminary data, we propose that opioids act
on the respiratory network collectively to cause respiratory depression rather than one area in isolation. There
are major voids in the understanding of opioid modulation of the respiratory circuitry, especially inhibition of
transmitter release. The goal of this proposal is to determine opioid regulation of identified projections
between respiratory controlling brainstem neurons in adult mice with fully developed respiratory circuitry. It
will focus on three brainstem areas that express mu opioid receptors and have dense reciprocal projections: the
preBötzinger complex and Bötzinger complex in the medulla and the KF in the pons. The hypothesis is that
presynaptic opioid receptors regulate synaptic connections between these areas to mediate opioid-induced
respiratory depression. A combination of approaches will be used to test this hypothesis on the cellular, circuit
and behavioral level. In Aim 1, opioid regulation of excitatory projections from the KF to the medulla will be
defined using brain slice electrophysiology and optogenetics. Then, in vivo experiments will test the role of
projections to the medulla in mediating respiratory depression caused by systemic opioid administration in
awake adult animals. In Aim 2, the opioid sensitivity of synapses from medullary projection neurons onto KF
neurons will be determined using brain slice electrophysiology and optogenetics. A unique arterially perfused
preparation that maintains an intact brainstem and “in vivo-like” respiratory cycle will be used to determine if
medullary projection neurons control the activity of single KF neurons. In Aim 3, the vulnerability of
presynaptic mu opioid receptors in the KF to chronic opioid treatment will be determined using brain slice
electrophysiology. Results from this project will provide mechanistic detail on opioid control of the
pontomedullary respiratory circuitry that leads to respiratory depression. This may help identify strategies to
counter opioid-induced respiratory depression and also inform on how synaptic mechanisms affect behavior.

## Key facts

- **NIH application ID:** 9893844
- **Project number:** 5R01DA047978-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Erica Sawyer Levitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,515
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893844

## Citation

> US National Institutes of Health, RePORTER application 9893844, Neural basis of opioid-induced respiratory depression (5R01DA047978-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893844. Licensed CC0.

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