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However, between 1999 and 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid-induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called \u2018biased agonists\u2019 that signal through some, but not all pathways downstream of the \u00b5-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced \u00df-arrestin 2 dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the \u2018biased agonist\u2019 approach, we re-examined breathing in \u00df-arrestin 2-deficient mice and instead find no connection between \u00df-arrestin 2 and opioid respiratory depression. This result suggests that any attenuated effect of \u2018biased agonists\u2019 on breathing is through an as-yet defined mechanism.<\/jats:p>","DOI":"10.7554\/elife.62552","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T08:00:38Z","timestamp":1621324838000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.62552","source":"Crossref","is-referenced-by-count":60,"title":["\u00df-arrestin 2 germline knockout does not attenuate opioid respiratory depression"],"prefix":"10.7554","volume":"10","author":[{"given":"Iris","family":"Bachmutsky","sequence":"first","affiliation":[{"name":"Department of Physiology, University of California, San Francisco","place":["San Francisco, United States"]},{"name":"Neuroscience Graduate Program, University of California, San Francisco","place":["San Francisco, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6621-3143","authenticated-orcid":true,"given":"Xin 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