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)
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.