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Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors.

Hildegard A Wulf, Caroline A Browne, Carlos A. Zarate, Irwin Lucki

Psychopharmacology July 2022 DOI: 10.1007/s00213-022-06118-4 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical study Peer reviewed
Population Mice
Interventions Ketamine (2R 6R)-hydroxynorketamine Naltrexone LY2444296
Dose Naltrexone 1 mg/kg; ketamine 10 mg/kg
Duration Behavioral testing 24 h post-treatment
Measures forced swim test
Topics Depression Ketamine Esketamine
Keywords Kappa opioid receptor Ly2444296 Naltrexone Repeated 2r,6r-hydroxynorketamine Repeated hnk Repeated ketamine
Key points Pretreatment with naltrexone (1 mg/kg) or the kappa opioid receptor antagonist LY2444296 blocked ketamine's (10 mg/kg) behavioral effect in the mouse forced swim test at 24 hours, and both pretreatments also blocked the immobility-reducing effect of (2R,6R)-hydroxynorketamine. The authors argue these data support a potential role for kappa opioid receptors in mediating the behavioral activity of ketamine and its metabolite.

Abstract

Emerging evidence has implicated the endogenous opioid system in mediating ketamine's antidepressant activity in subjects with major depressive disorder. To date, mu opioid receptors have been suggested as the primary opioid receptor of interest. However, this hypothesis relies primarily on observations that the opioid antagonist naltrexone blocked the effects of ketamine in humans and rodents. This report confirms previous findings that pretreatment with naltrexone (1 mg/kg) just prior to ketamine (10 mg/kg) administration effectively blocks the behavioral effect of ketamine in the mouse forced swim test 24 h post-treatment. Furthermore, pharmacological blockade of kappa opioid receptors prior to ketamine administration with the selective, short-acting antagonist LY2444296 successfully blocked ketamine's effects in the forced swim test. Likewise, the ability of the ketamine metabolite (2R,6R)-hydroxynorketamine to reduce immobility scores in the forced swim test was also blocked following pretreatment with either naltrexone or LY2444296. These data support a potential role of kappa opioid receptors in mediating the behavioral activity of ketamine and its non-dissociate metabolite (2R,6R)-hydroxynorketamine.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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