Harnessing genetic variation in the laboratory mouse to discover the mechanisms of opioid overdose

PiezoSleepTM Enables Large Scale Study to Identify Heritable Differences Responsible for Morphine Sensitivity and Respiratory Depression

A large scale genetic study conducted by researchers at The Jackson Laboratory used Signal Solutions’ PiezoSleepTM system as a noninvasive breath tracking method to identify genetic regions associated with morphine induced respiratory depression.  Breathing data was collected continuously from cages using the PiezoSleepTM system before and after morphine administration from over 300 Diversity Outbred (DO) mice, representing recombinants from the eight inbred founder strains (founder strains for Collaborative Cross and DO mice). A baseline average breath rate was estimated from piezo breath signals during periods of low activity over twenty-four hours prior to morphine administration, and respiratory response to morphine was calculated as the percent of baseline respiratory rate following morphine administration. Breath rate monitoring with the PiezoSleepTM system pinpointed a chromosomal region that is highly associated with reduced breath rate following morphine administration.

Phenotyping the breath response in the 300 Diversity Outbred mice, combined with high density genotyping, mapped morphine response to specific chromosomal regions. Four Quantitative Trait Loci (QTL) were identified for respiratory response to morphine, including a strong QTL on chromosome five (LOD 9.2 QTL at Chromosome 5:24.98-26.16 MBp), driven by strong NOD vs WSB/Eij allele effects. Strain specific polymorphisms within the stretch of DNA identified a candidate gene, Galnt11 (N-acetylgalactosaminyltrasferase 11), based on expression pattern in breath regulatory regions, relevance of biological function, and expected functional change of the encoded protein due to the identified polymorphism. Follow-up studies are in progress.

See the full published study: Genetic variation regulates opioid-induced respiratory depression in mice  Bubier, et. Al. Scientific Reports, natureresearch Sep 11 2020

Respiratory depression is the main cause of death in opioid overdoses, averaging 45,000 deaths each year in the USA over the last five years. Jason Bubier and Elissa Chesler of The Jackson Laboratory are leading an NIH funded multi-year effort to identify genes that are involved in opioid induced respiratory depression, with hopes of better treatment and assessing patient risks for prescription pain medication. https://www.jax.org/news-and-insights/2020/april/preventing-overdose-deaths

This research program, funded by The National Institute of Drug Abuse (grant # R01DA048890), will expand the investigation of opioid response in Diversity Outbred mice beyond morphine to the much more dangerous synthetic opioid, Fentanyl.  Candidate genes will be tested by engineering allelic variants into different genetic backgrounds using CRISPR/Cas9 technology. Functional breathing differences in response to morphine and fentanyl in the DO and engineered mice will be assessed with PiezoSleepTM.