{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:53:56Z","timestamp":1769838836900,"version":"3.49.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Ketamine has been shown to produce analgesia in various acute and chronic pain states; however, abuse liability concerns have limited its utility. The ketamine metabolite (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-hydroxynorketamine (HNK) has been shown to produce antidepressant-like effects similar to ketamine without abuse liability concerns. (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK produces sustained analgesia in models of chronic pain, but has yet to be evaluated in models of acute pain. The present study evaluated the efficacy of acute (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK administration (one injection) in assays of pain-stimulated (52- and 56-degree hot plate test and acetic acid writhing) and pain-depressed behavior (locomotor activity and rearing) in male and female C57BL\/6 mice. In assays of pain-stimulated behaviors, (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK (1\u201332 mg\/kg) failed to produce antinociception in the 52- and 56-degree hot plate and acetic acid writhing assays. In assays of pain-depressed behaviors, 0.56% acetic acid produced a robust depression of locomotor activity and rearing that was not blocked by pretreatment of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK (3.2\u201332 mg\/kg). The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Finally, the effects of intermittent (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK administration were evaluated in 52-degree hot plate and pain-depressed locomotor activity and rearing. Intermittent administration of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2<jats:italic>R<\/jats:italic>,6<jats:italic>R<\/jats:italic>)-HNK in chronic pain states should continue to be evaluated.<\/jats:p>","DOI":"10.1371\/journal.pone.0301848","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T17:22:39Z","timestamp":1713547359000},"page":"e0301848","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice"],"prefix":"10.1371","volume":"19","author":[{"given":"Todd M.","family":"Hillhouse","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaitlyn J.","family":"Partridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-9166","authenticated-orcid":true,"given":"Patrick I.","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah C.","family":"Honeycutt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-1383","authenticated-orcid":true,"given":"Joseph H.","family":"Porter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"pone.0301848.ref001","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.15585\/mmwr.mm6736a2","article-title":"Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults\u2014United States, 2016","volume":"67","author":"J 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