Document Type

Article

Publication Date

9-11-2020

Keywords

JMG, JAXCC

JAX Source

Sci Rep 2020 Sep 11; 10(1):14970

PMID

32917924

DOI

https://doi.org/10.1038/s41598-020-71804-2

Grant

DA037927,AA018776,DA039841,DA048890

Abstract

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. The diversion and misuse of prescription opioids along with increased use of drugs like heroin and fentanyl, has led to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse population, the Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. We used DO mice treated with morphine to map quantitative trait loci for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicate Galnt11, an N-acetylgalactosaminyltransferase, as a gene that regulates OIRD.

Comments

Special thanks to Jennifer Ryan and the Center for Biometric analysis at JAX for use of the PiezoSleep system and to Stephen Krasinski for extensive edits of the manuscript.

This article is licensed under a Creative Commons Attribution 4.0 International License.

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