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.
Highlights
In the U.S, opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014
We investigated the effect of genetic variation on opioid-induced respiratory depression (OIRD) and lethality in the founders of the advanced, high-diversity mouse populations, the Collaborative Cross (CC) and Diversity Outbred (DO) populations
We found heritable strain differences in the quantitative metrics of respiratory response to morphine, including respiratory depression, recovery time and survival time, using an advanced, high-throughput, behavioral phenotyping protocol
Summary
In the U.S, opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. One study found that a strain harboring an OPRM1 hypomorph (CXB7), in which OPRM1 gene function is reduced, have a much higher L D50 for morphine than strains with intact mu-opioid[8,24], confirming the importance of OPRM1 in opioid-induced lethality and revealing strain diversity in the mu-opioid receptor locus. Together, these studies show that variation in response to opioids is associated with differences in strain, indicating that responses to opioids are genetically influenced phenotypes. Endpoint, and did not characterize known sex differences in opioid s ensitivity[26] and were not designed to define the genetic loci or the underlying biological mechanisms responsible for the strain variation in complex opioid responses, such as respiratory depression
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