# Mechanism and Countermeasure of Fentanyl-Induced Sudden Death

> **NIH NIH R01** · LOVELACE BIOMEDICAL RESEARCH INSTITUTE · 2024 · $897,591

## Abstract

PROJECT SUMMARY
Opioids were involved in 75,673 overdose deaths in 2020 in the U.S. Fentanyl, an opioid mu-receptor (MOR)
agonist acting on central MORs produces analgesia, but depresses ventilation that could be lethal. Rapid
intravenous injection of overdose fentanyl, particularly in Illicit use, is the deadliest. It triggers an apnea leading
to sudden death within minutes in ~1/3 of adults (male > female) with ~75% of fentanyl sequestered by the lungs
after injection. Naloxone is the preferable treatment for post-overdose, but not viable for the illicit FNT users who
are found pulseless upon the arrival of emergency medical services. Moreover, naloxone counteracts analgesia
with potentially life-threatening side effects. Central apnea, upper airway obstruction, and chest wall rigidity are
assumed to be accountable for the sudden death, but the exact cause of the death and the effective
countermeasure remain unknown, constituting a critical and unmet therapeutic clinical need.
Bronchopulmonary C-fibers (PCFs) are the major sensory nerve endings innervating the airways and lungs and
crucial in the control of respiratory rhythm. PCF stimulation could elicit central apnea and vocal closure likely by
promoting release of glutamate or substance P to activate PCF 2nd-order neurons in the nucleus tractus solitarius
via AMPA and neurokinin-1 receptor. We have reported that intravenous bolus injection of a low dose fentanyl
triggers a PCF-mediated brief apnea, consistent with previously reported excitation of dorsal root ganglion C-
neurons by MOR agonists via Gs-cAMP pathway. Our preliminary data show a triple apnea (central apnea, vocal
closure and laryngeal constriction/collapse) coupled with chest wall rigidity, resulting in death within minutes in
anesthetized adult rats after overdose fentanyl is rapidly injected. In this proposal, we seek to establish the first
animal model of fentanyl-induced sudden death following triple apnea in awake adult rats and determine the
dependency of triple apnea (death) on the gender and peripheral (especially vagal) MORs/µ1Rs (Aim 1). We will
further demonstrate that fentanyl directly stimulates PCFs to evoke triple apnea by acting on MOR/µ1R and Gs-
cAMP pathway, thereby promote PCF release of glutamate and SP to activate the 2nd-order neurons (Aim 2).
Our pilot study has shown that intravenous injection of dermorphin (a peripherally acting MOR agonist) induces
MOR internalization in vagal sensory neurons and blocks fentanyl-induced triple apnea. The β-arrestin-mediated
signaling is known to be responsible for MOR desensitization/internalization. We will define that diamorphine has
limited impact on baseline cardiorespiratory activity, but internalizes PCFs' MORs/µ1Rs via activation of β-
arrestin-signaling to prevents the triple apnea (death) with no change in analgesia. This will present a potential
safer and translational pretreatment for overdose fentanyl in clinical settings (Aim 3). A multidisciplinary appro...

## Key facts

- **NIH application ID:** 10757945
- **Project number:** 5R01HL163512-02
- **Recipient organization:** LOVELACE BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Fadi Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $897,591
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757945

## Citation

> US National Institutes of Health, RePORTER application 10757945, Mechanism and Countermeasure of Fentanyl-Induced Sudden Death (5R01HL163512-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757945. Licensed CC0.

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