# Unraveling the dynamic mechanisms underlying opioid respiratory depression

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $792,362

## Abstract

PROJECT SUMMARY
The opioid epidemic claims more than 50,000 lives every year and contributes to a significant drop in overall
life expectancy in the USA. The primary cause of death associated with opioid-based analgesics and drugs of
abuse is Opioid-mediated Respiratory Suppression (ORS). Although, the mortality risk increases in a dose-
dependent manner, opioid use is particularly dangerous because it is unpredictable. Many conditions increase
the vulnerability to opioids, including sleep disordered breathing, which is very common among opioid users.
Opioids cause respiratory depression and terminal apnea by inhibiting rhythmogenic networks within the
ventrolateral medulla. This project has 4 aims to explore the medullary mechanisms underlying ORS. Aim 1
employs a variety of electrophysiological, pharmacological, and optogenetic approaches in vitro and in vivo to
explore how opioids inhibit the inspiratory rhythmogenic network. This opioid-sensitive network forms a column
that dynamically extends beyond the well-known preBötzinger complex, a microcircuit that is essential for
breathing. Aim 2 will obtain horizontal slices from this rhythmogenic column to dissect the pre-and postsynaptic
mechanisms that are responsible for the cessation of inspiratory activity. Aim 3 will investigate how opioids
inhibit Postinspiration within the postinspiratory complex (PiCo), an excitatory network that is an order of
magnitude more sensitive to opioids than the preBötC. The mechanisms revealed in aim 1-3 will provide the
basis for aim 4, which will explore combinations of substances capable of reversing ORS in alert animals. This
project introduces novel concepts of respiratory rhythmogenesis and describes multiple mechanisms of opioid
actions, which could explain why opioid respiratory depression is so unpredictable. We test how opioid
modulation is sensitized by hypercapnic conditions and chronic intermittent hypoxia, both conditions are often
experienced by opioid users. The proposed research may lead to a better understanding of the mechanisms
underlying the mortality and morbidity associated with the opioid crisis.

## Key facts

- **NIH application ID:** 9843730
- **Project number:** 5R01HL144801-02
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Jan M. Ramirez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $792,362
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843730

## Citation

> US National Institutes of Health, RePORTER application 9843730, Unraveling the dynamic mechanisms underlying opioid respiratory depression (5R01HL144801-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9843730. Licensed CC0.

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