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The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti\u2010nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Respiration was measured in awake, freely moving male CD\u20101 mice using whole body plethysmography. Anti\u2010nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR\u201017018 were administered orally. Receptor activation and arrestin\u20103 recruitment were measured in HEK293 cells using BRET assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Across the dose ranges examined, all opioids studied depressed respiration in a dose\u2010dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR\u201017018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti\u2010nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>In addition to providing effective anti\u2010nociception, the novel opioids, oliceridine, tianeptine and SR\u201017018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16199","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T06:24:54Z","timestamp":1690266294000},"page":"3160-3174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Assessment of the potential of novel and classical opioids to induce respiratory depression in mice"],"prefix":"10.1111","volume":"180","author":[{"given":"Rob","family":"Hill","sequence":"first","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre University of Nottingham  Nottingham UK"},{"name":"Centre of Membrane Proteins and Receptors, Universities of Nottingham and Birmingham  Midlands UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre University of Nottingham  Nottingham UK"},{"name":"Centre of Membrane Proteins and Receptors, Universities of Nottingham and Birmingham  Midlands UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lemel","sequence":"additional","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre University of Nottingham  Nottingham UK"},{"name":"Centre of Membrane Proteins and Receptors, Universities of Nottingham and Birmingham  Midlands UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana","family":"Antonijevic","sequence":"additional","affiliation":[{"name":"Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute University Park  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yselkla","family":"Hosking","sequence":"additional","affiliation":[{"name":"Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute University Park  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailesh N.","family":"Mistry","sequence":"additional","affiliation":[{"name":"Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham Biodiscovery Institute University Park  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Kruegel","sequence":"additional","affiliation":[{"name":"Department of Chemistry Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Javitch","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry and Molecular Pharmacology and Therapeutics Columbia University Vagelos College of Physicians &amp; Surgeons  New York New York USA"},{"name":"Division of Molecular Therapeutics New York State Psychiatric Institute  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-7875","authenticated-orcid":false,"given":"J. 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