Genetic Variation Regulates Opioid-Induced Respiratory Depression in Mice

Bubier, Jason A.; He, Hao; Philip, Vivek M.; Roy, Tyler; Hernandez, Christian Monroy; Donohue, Kevin D.; O’Hara, Bruce F.; Chesler, Elissa A

doi:10.1101/2020.06.15.152249

Cited by 5 publications

(5 citation statements)

References 66 publications

(55 reference statements)

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“…An absence of tolerance to morphine antinociception in a related 129 mouse substrain has also been shown in multiple studies [84]. In terms of side effects, a recent study showed that the sensitivity of 129 substrain animals to lethal morphine respiratory depression was lower than that of C57BL/6 mice [85]. This evidence of strain variation in opioid response suggests that the dramatic β-arrestin2-knockout phenotype initially observed was substantially confounded by parental 129/SvJ strain characteristics segregating with the knockout locus.…”

Section: Trends Trends In In Pharmacologicalmentioning

confidence: 70%

Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

Gillis

Kliewer

Kelly

et al. 2020

Trends in Pharmacological Sciences

107

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G protein-biased agonists of the μ-opioid receptor (MOPr) have been proposed as an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the β-arrestin2-knockout mouse that led to this proposal, and alternative genetic models do not support the G proteinbiased MOPr agonist hypothesis. Furthermore, assessment of putatively biased ligands has been confounded by several factors, including assay amplification. As such, the extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that β-arrestin2 mediates deleterious opioid effects. Addressing these current challenges represents a pressing issue to successfully advance drug development at this receptor and improve upon current opioid analgesics. Current View of MOPr Biased SignalingG protein-biased agonists (see Glossary) of the μ-opioid receptor (MOPr) have been widely proposed to be a novel, substantially improved class of analgesics [1,2]. The prototypical such agonist, oliceridine (TRV130), has proceeded to Phase III clinical trials [3], and was recently approved in the USA for use in acute pain. Existing, clinically approved opioid analgesics, such as morphine, oxycodone, and fentanyl, are MOPr agonists that provide pain relief that is unmatched by other drug classes. Current opioids have an array of adverse effects, including respiratory depression, constipation, and euphoria, as well as inducing tolerance and dependence over time. These important limitations of opioid analgesics have all been proposed to be addressed by G protein-biased MOPr agonists (Box 1). However, recent results have brought into question the hypothesis that underpins the proposed mechanism of action of this anticipated new drug class, that β-arrestin2 mediates deleterious opioid effects. In addition, there is evidence that challenges both the extent of the G protein bias of lead compounds and the extent to which such compounds are likely to represent improved analgesics.

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Section: Trends Trends In In Pharmacologicalmentioning

confidence: 70%

Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

Gillis

Kliewer

Kelly

et al. 2020

Trends in Pharmacological Sciences

107

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“…Breathing behaviors and OIRD severity differ between strains of mice 19 . Therefore, we sought to compare basal and morphine modulated breathing in mice with the same genetic background.…”

Section: Resultsmentioning

confidence: 96%

“…This study was designed with four important features: First, we compared littermates in order to control for strain specific effects on breathing and opioid sensitivity 19 . Second, the comparison of breathing after IP injection of saline and morphine in the same animal controls for any within-animal specific breathing patterns.…”

Section: Discussionmentioning

confidence: 99%

ß2-Arrestin germline knockout does not attenuate opioid respiratory depression

Bachmutsky

Durand

Yackle

2020

Preprint

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Opioids are perhaps the most effective analgesics in medicine. However, from 1999 to 2018, they also killed more than 400,000 people in the United States by suppressing breathing, a common side-effect known as opioid induced respiratory depression. This doubled-edged sword has inspired the dream of developing novel therapeutics that provide opioid-like analgesia without respiratory depression. One such approach has been to develop so-called ‘biased agonists’ that activate some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This hypothesis stems from a study suggesting that MOR-mediated activation of ß2-Arrestin is the downstream signaling pathway responsible for respiratory depression, whereas inhibition of adenylyl cyclase produces analgesia. To further verify this model, which represents the motivation for the biased agonist approach, we examined respiratory behavior in mice lacking the gene for ß2-Arrestin. Contrary to previous findings, we find no correlation between ß2-Arrestin function and opioid-induced respiratory depression, suggesting that any effect of biased agonists must be mediated through an as-yet to be identified signaling mechanism.

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“…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.…”

Section: Open Accessmentioning

confidence: 96%