Genetic variation regulates opioid-induced respiratory depression in mice

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.

ß-arrestin 2 germline knockout does not attenuate opioid respiratory depression

“…Breathing behaviors and OIRD severity differ between strains of mice ( Bubier et al, 2020 ). Therefore, we sought to compare basal and morphine depressed breathing in mice with the same genetic background.…”

“…Unlike other studies, we designed ours with five important features to ensure a robust conclusion. First, the OIRD comparisons were made between littermates in an effort to control for any strain specific effects on breathing and opioid sensitivity ( Bubier et al, 2020 ). Second, OIRD was defined as the comparison of breathing after IP injection of saline and morphine in the same animal to control for any within-animal specific breathing variation.…”

Intranasal leptin improves survival after opioid overdose in a mouse model

“…Data from previous studies showing that leptin mitigates the effects of opioids by improving upper airway patency and control of breathing suggest that decrease in mortality is mainly due to attenuation of respiratory failure [ 3 ]. However, Bubier et al did not observe a correlation between respiratory depression, recovery time and survival time in different mouse strains [ 7 ]. Thus, the adverse effects of morphine on other systems may play a role in morphine induced mortality.…”

Biased Opioid Ligands: Revolution or Evolution?

“…Thus, the first results obtained by Bohn and co-workers on beta-arrestin 2 knockout animals were obtained on a mixed genetic background (beta-arrestin 2 knockout 129/SvJ backcrossed with C57BL6). Previous studies reported that the 129/SvJ mice have a higher sensitivity to morphine-induced antinociception ( 36 ), did not develop tolerance to morphine-induced analgesia ( 37 ) and were less sensitive to respiratory depression ( 38 ). When reassessing the pharmacological responses induced by opioids in beta-arrestin 2 knockout using an homogenous C57BL6 background, Koblich and colleagues did not find any difference in tolerance to analgesic effects of few opioids including morphine ( 39 ).…”