# Investigating the mechanistic consequences of fentanyl-induced hypoxia and cardiorespiratory collapse

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $453,600

## Abstract

PROJECT SUMMARY
Acute exposure to ultrapotent synthetic opioids (UPSO), such as fentanyl, represents a significant public health
concern. In the ongoing opioid epidemic, it is estimated that UPSO exposure contributes to over 80% of
overdose-related deaths. The current defense strategy against UPSO exposure has been the development of
reversal agents, such as naloxone, that aim to effectively reverse opioid-induced respiratory depression and
related secondary complications with breathing. However, the high potency of UPSO decreases the window of
time in which a counteragent can be administered before UPSO-dependent cardiorespiratory collapse (CRC)
occurs and immediate resuscitative action is required. Optimal strategies for resuscitation following UPSO-
dependent CRC are unknown. Resuscitation increases the risk for hypoxic-ischemic reperfusion injury (HIRI),
which can lead to additional morbidity and death despite reversal of the opioid-mediated effects on breathing.
Critical knowledge gaps exist in understanding how UPSO exposure impacts post-resuscitative outcomes in vital
organ systems such as the heart, lungs, and brain. These gaps are a significant roadblock to successfully
minimizing the morbidities and mortalities associated with UPSO exposure. Proposal Objective: Establish a
foundational understanding of the cellular and systemic outcomes after reversing fentanyl-induced CRC (fiCRC).
We have developed a novel model of fiCRC where we observe pulmonary edema following naloxone
administration and reversal of respiratory depression, closely modeling documented clinical observations.
Central Hypothesis: Factors beyond respiratory depression contribute to the progression of fentanyl overdose,
leading to injury following the reversal of fiCRC; these factors are tractable targets in minimizing injury due to
fentanyl overdose and its reversal. We propose the following aims to test this. Aim 1: Characterize how fentanyl
and the reversal of OIRD impact the relationship between breathing and O2 consumption, mitochondrial activity,
and tissue-specific glucose metabolism. Aim 2: Characterize physiological outcomes of fentanyl overdose and
reversal of fiCRC in the cardiopulmonary system and brain. Aim 3: Test the efficacy of adjunctive strategies
during naloxone-mediated reversal of fiCRC to improve outcomes in the cardiopulmonary system and brain. This
proposal and its aims align with RFA-DA-23-056 to support mechanistic investigations into persistent/delayed
pathophysiological effects following acute UPSO exposure.

## Key facts

- **NIH application ID:** 10990023
- **Project number:** 1R01DA061412-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Alfredo J Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,600
- **Award type:** 1
- **Project period:** 2024-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990023

## Citation

> US National Institutes of Health, RePORTER application 10990023, Investigating the mechanistic consequences of fentanyl-induced hypoxia and cardiorespiratory collapse (1R01DA061412-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10990023. Licensed CC0.

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