Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Proceedings of the National Academy of Sciences of the United States of America January 15, 2020 Matthew E. Klein, Joshua Chandra, Salma A. Sheriff et al. 157 citations
Ketamine, a rapid antidepressant for treatment-resistant depression, requires functional opioid receptors to produce its effects, but it does not act as an opioid itself. In rodent models, blocking opioid receptors prevented ketamine's antidepressant-like behavioral and cellular effects, while activating opioid receptors alone caused hedonic responses and failed to alleviate anhedonia. Ketamine's cellular actions were mimicked by an NMDA receptor antagonist but not by a μ-opioid agonist. The findings suggest that ketamine's antidepressant action depends on both NMDA and opioid receptor signaling, with opioid receptors playing a permissive role rather than mediating the effects directly.