# Genetic Variation in Opioid Induced Respiratory Depression in Mice

> **NIH NIH R01** · JACKSON LABORATORY · 2021 · $710,039

## Abstract

PROJECT SUMMARY/ABSTRACT
Prescription of opioids for treatment of pain has nearly quadrupled from 1999 to 2014 leading to an epidemic in
addiction and overdose deaths in the United States. Morphine and its synthetic and more potent counterpart,
fentanyl, bind to opioid receptors in the peripheral and central nervous system, producing feelings of sedation
and euphoria in addition to analgesia. Opioid-induced respiratory depression (OIRD) caused by the activation
of opioid receptors on neurons in the brainstem respiratory centers may lead to cardiorespiratory collapse and
ultimately death. Naloxone, a competitive opioid receptor antagonist used to treat opioid overdose, blocks the
effects of opioids but may cause rapid and severe opioid withdrawal, which is itself a medical emergency.
There is substantial inter-individual variation in response to opioids, resulting in variation in sensitivities to
opioid overdose and treatment responses. However, the collection of factors and underlying mechanisms that
determine the variable responses to opioids remain unknown. The long-term goal is to define the biological
basis of opioid overdose risk and to discover safe and effective novel reversal agents. The overall objective of
this proposal is to define the molecular mechanisms underlying individual variability in respiratory responses to
opioids that indicate specific sensitivities to opioids and pharmacological alternatives to naloxone. Preliminary
studies using the founders of the advanced, high-diversity mouse populations, the Collaborative Cross (CC)
and Diversity Outbred (DO), have revealed strain differences in opiate lethality and respiratory sensitivity
modeling the individual variability to OIRD in humans. The overall objective will be attained by pursuing three
specific aims: 1) Map genetic loci that underlie the variability in morphine and fentanyl sensitivity in the DO
mouse population; 2) Define the in depth physiological components of OIRD in CC mice using PiezoSleep and
plethysmography; and 3) Define the mechanisms that underlie the variable response to morphine and fentanyl
by profiling the brainstem transcriptome in CC mice. Under the first aim, quantitative trait loci for survival time,
recovery time and depth or respiratory depression due to morphine or fentanyl treatment will be mapped in the
DO population. Under the second aim, comprehensive respiratory phenotyping will be performed in naïve,
morphine-treated and fentanyl-treated CC mice. Under the third aim, expression QTL in the CC mice will be
mapped, gene co-expression network modeling will be performed, and gene expression will be correlated with
phenotypic variation. The proposed research is innovative because it represents a new and substantive
departure from the status quo by using methods that enable unbiased discovery of new pathways and
mechanisms of opioid overdose vulnerability and remediation. The proposed study is significant because
understanding the mechanisms that und...

## Key facts

- **NIH application ID:** 10131786
- **Project number:** 5R01DA048890-02
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Jason A Bubier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $710,039
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131786

## Citation

> US National Institutes of Health, RePORTER application 10131786, Genetic Variation in Opioid Induced Respiratory Depression in Mice (5R01DA048890-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10131786. Licensed CC0.

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