# Recruiting active expiration to overcome opioid-induced persistent apnea

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $156,000

## Abstract

ABSTRACT
While prescription opioids are exceptional analgesics, they have significant side effects, especially opioid-induced
persistent apnea (OIPA). A significant public health problem follows from these side effects, as overdoses caused almost
50,000 deaths in 2019, along with non-fatal overdoses that result in costly and often extended hospitalization. The
“opioid epidemic” accelerated further during the COVID-19 pandemic, with a 38% increase in deaths due to synthetic
opioid overdose (primarily fentanyl) compared to 2019. We propose a logical path to identifying molecules that can
engage active expiration, thereby increasing tolerance of opioids. Those molecules may supplement current treatments
for OIPA, e.g., higher efficacy and safety, longer half-life, possibly preserving opioid-induced analgesia. Opioids depress
breathing by actions on inspiratory rhythm generating regions, the preBötzinger Complex (preBötC), either directly by
activating µ-opioid receptors (µORs) in preBötC, or indirectly by inhibiting tonic drive from the Parabrachial Nuclei to
preBötC. µORs are inhibitory G-protein coupled receptors (GPCRs) that depress neuronal excitability. Parafacial
respiratory group (pF) contains an active expiratory oscillator, which is independent of preBötC, is opioid-insensitive and
is silent at rest, but can become active during certain conditions, e.g. exercise, high CO2. When it is active, it is tightly
coupled to inspiration. We propose to express excitatory GPCR HM3Dq receptors (designer receptors exclusively
activated by designer drugs) in pF and test whether activation of these receptors increases the dose of fentanyl required
to produce persistent apnea. We will then sequence the pF neurons to determine expression of endogenous excitatory
GPCRs and test the efficacy of the agonists of these GPCRs in increasing the dose of fentanyl required to produce
persistent apnea in anesthetized mice. Success of this exploratory project will generate data for subsequent preclinical
and translational investigation of agonists of these receptors as potential therapeutics for preventing OIPA.

## Key facts

- **NIH application ID:** 10656563
- **Project number:** 5R21DA056740-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** JACK L FELDMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $156,000
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656563

## Citation

> US National Institutes of Health, RePORTER application 10656563, Recruiting active expiration to overcome opioid-induced persistent apnea (5R21DA056740-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10656563. Licensed CC0.

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