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bioRxiv · 10.1101/2020.08.28.272575

β2-Arrestin germline knockout does not attenuate opioid respiratory depression

Bachmutsky, I.·Durand, A.·Yackle, K.
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Abstract

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 {micro}-opioid receptor (MOR), the target of morphine and other opioid analgesics. This hypothesis stems from a study suggesting that MOR-mediated activation of {beta}2-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 {beta}2-Arrestin. Contrary to previous findings, we find no correlation between {beta}2-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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Bachmutsky, I., Durand, A., Yackle, K.. 2020-08-28. β2-Arrestin germline knockout does not attenuate opioid respiratory depression. https://doi.org/10.1101/2020.08.28.272575

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