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Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)\u2010hydroxynorketamine (6\u2010hydroxynorketamine) is not an<jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>antagonist. However, it may modulate nociception through negative allosteric modulation of \u03b17 nicotinic acetylcholine receptors. We studied whether 6\u2010hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6\u2010hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high\u2010performance liquid chromatography\u2013tandem mass spectrometry. Ketamine (10 mg\/kg), but not 6\u2010hydroxynorketamine (10 and 30 mg\/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6\u2010hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6\u2010hydroxynorketamine were doubled by morphine pre\u2010treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co\u2010administration of 6\u2010hydroxynorketamine 20 mg\/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6\u2010hydroxynorketamine brain concentrations were increased after co\u2010administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6\u2010hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.<\/jats:p>","DOI":"10.1111\/bcpt.12941","type":"journal-article","created":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T05:57:16Z","timestamp":1511503036000},"page":"481-488","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interactions of (2S,6S;2R,6R)\u2010Hydroxynorketamine, a Secondary Metabolite of (R,S)\u2010Ketamine, with Morphine"],"prefix":"10.1111","volume":"122","author":[{"given":"Tuomas O.","family":"Lilius","sequence":"first","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"},{"name":"Department of Clinical Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland"},{"name":"HUSLAB Helsinki University Hospital Helsinki 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