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. 2025 Aug;182(15):3428-3451.
doi: 10.1111/bph.70018. Epub 2025 Mar 28.

(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice

Andria Michael  1   2 , Anna Onisiforou  1   2 , Polymnia Georgiou  3 , Morfeas Koumas  4 , Chris Powels  5 , Elmar Mammadov  5 , Andrea N Georgiou  1   2 , Panos Zanos  1   2   5
Affiliations

(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice

Andria Michael et al. Br J Pharmacol. 2025 Aug.

Abstract

Background and purpose: Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.

Experimental approach: Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.

Key results: (2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.

Conclusions and implications: These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related 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.

Keywords: abstinence; addiction; comorbidities; depression; mice; negative affect; opioid use disorders; opioids; rodent models.

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