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Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Using mouse models, we investigated the effects of ketamine's metabolite (<jats:italic>2R,6R<\/jats:italic>)\u2010hydroxynorketamine (HNK) on reversing conditioning to sub\u2010effective doses of morphine in stress\u2010susceptible mice, preventing conditioned\u2010place aversion and alleviating acute somatic abstinence symptoms in opioid\u2010dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety\u2010like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>(<jats:italic>2R,6R<\/jats:italic>)\u2010HNK reversed conditioning to sub\u2010effective doses of morphine in stress\u2010susceptible mice and prevented conditioned\u2010place aversion and acute somatic abstinence symptoms in opioid\u2010dependent mice. In addition, (<jats:italic>2R,6R<\/jats:italic>)\u2010HNK reversed anhedonia, anxiety\u2010like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high\u2010frequency EEG oscillations, through a GluN2A\u2010NMDA receptor\u2010dependent mechanism. Notably, (<jats:italic>2R,6R<\/jats:italic>)\u2010HNK facilitated the extinction of opioid conditioning, prevented stress\u2010induced reinstatement of opioid\u2010seeking behaviours and reduced the propensity for enhanced morphine self\u2010consumption in mice previously exposed to opioids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These findings emphasize the therapeutic potential of (<jats:italic>2R,6R<\/jats:italic>)\u2010HNK, which is currently in Phase II clinical trials, in addressing stress\u2010related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70018","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T04:17:39Z","timestamp":1743394659000},"page":"3428-3451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["(<i>2R,6R<\/i>)\u2010hydroxynorketamine prevents opioid abstinence\u2010related negative affect and stress\u2010induced reinstatement in mice"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8193-8423","authenticated-orcid":false,"given":"Andria","family":"Michael","sequence":"first","affiliation":[{"name":"Department of Psychology University of Cyprus  Nicosia Cyprus"},{"name":"Center for Applied Neuroscience (CAN) University of Cyprus  Nicosia 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