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

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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.

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Funding

The authors were supported by the United States Public Health Service (USPHS) grant R01 MH105623 and Transforming Technology for the Warfighter Program grant number HU00012020014, which were administered by the Henry M Jackson Foundation for the Advancement of Military Medicine. The funding sponsors were not involved in the preparation or submission of the article for publication. We are grateful to Drs. Craig J. Thomas of the National Center for Advancing Translational Sciences for his help in obtaining 2R,6R-hydroxynorketamine and for helpful comments on this manuscript.

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  1. Department of Pharmacology and Molecular Therapeutics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Hildegard A. Wulf, Caroline A. Browne & Irwin Lucki

  2. National Institute on Mental Health, MD, 20814, Bethesda, USA

    Carlos A. Zarate

  3. Department of Psychiatry, Uniformed Services University, Bethesda, MD, 20814, USA

    Irwin Lucki

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  1. Hildegard A. Wulf
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  2. Caroline A. Browne
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  3. Carlos A. Zarate
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Correspondence to Caroline A. Browne or Irwin Lucki.

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Wulf, H.A., Browne, C.A., Zarate, C.A. et al. Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors. Psychopharmacology 239, 2309–2316 (2022). https://doi.org/10.1007/s00213-022-06118-4

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