# Brainstem mechanisms of opioid-induced respiratory depression

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $537,188

## Abstract

Project Summary
Opioid overdoses continue to rise at an alarming rate in the US. Respiratory failure is the cause of death from
opioid overdose. Yet, the mechanisms by which respiratory depression and cessation of breathing occur are
poorly understood. Emerging evidence from our lab and others implicates mu opioid receptors expressed
throughout the brainstem control of breathing network, including areas in the dorsolateral pons and the
ventrolateral medulla. Recently, we have found that opioids selectively suppress an excitatory pontomedullary
circuit, which could disrupt the delicately balanced neurotransmission that is required for proper breathing.
However, opioid-sensitive neurons only account for approximately half of the pontomedullary respiratory
neurons. We propose that to fully understand the effect of opioids on breathing we must also consider the
activity of neurons that are not inhibited by opioids and continue to function unopposed. We know from
published and preliminary data that non-opioid-sensitive pontine neurons project to medullary respiratory
centers, but do not synapse onto excitatory neurons. In addition, most non-opioid-sensitive pontine neurons
are expiratory and continue to fire during opioid overdose. Thus, we hypothesize that expiratory, non-opioid-
sensitive pontine neurons contribute to breathing failure via tonic glutamatergic projections to inhibitory
neurons in the ventrolateral medulla. We will test this hypothesis in adult mice with fully developed respiratory
circuitry using cell-type and projection specific approaches at the cellular, circuit and in vivo level in three
specific aims. Aim 1 will determine the synaptic target of non-MOR-expressing dorsolateral pontine neurons
using optogenetics and ex vivo recordings of fluorescently labeled inhibitory neurons in the ventrolateral
medulla. Aim 2 will determine the respiratory phenotype of opioid-insensitive, glutamatergic, medullary
projecting dorsolateral pontine neurons using single unit recording of optically-tagged neurons in a unique
arterially perfused mouse preparation that maintains an intact brainstem and “in vivo-like” respiratory cycle.
Aim 3 will use intersectional genetics to optically stimulate or inhibit medullary projecting, non-opioid-sensitive
dorsolateral pontine neurons in arterially perfused preparations and in vivo to determine the ability of these
neurons to promote or prevent apnea. Together, this R01 project will contribute to our long-term goal to
generate a more complete model of the brain’s control of breathing network under different influences, such as
opioids, and can be expanded upon in future studies based on this research.

## Key facts

- **NIH application ID:** 10938156
- **Project number:** 1R01HL174547-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Erica Sawyer Levitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,188
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938156

## Citation

> US National Institutes of Health, RePORTER application 10938156, Brainstem mechanisms of opioid-induced respiratory depression (1R01HL174547-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10938156. Licensed CC0.

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