The endogenous opioid system in the medial prefrontal cortex mediates ketamine's antidepressant-like actions.
Cheng Jiang, Ralph Dileone, Christopher Pittenger, Ronald S. Duman
Translational Psychiatry February 12, 2024 DOI: 10.1038/s41398-024-02796-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine Naltrexone |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressants Brain chemistry Mental health |
| Citations | 37 |
| Key findings | Β-endorphin and activation of opioid receptors in the medial prefrontal cortex are required for the antidepressant-like effects of ketamine in rats. |
Abstract
Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) are blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupts the behavioral effects of ketamine. Ketamine treatment rapidly increases levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolishes both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 26
- Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions? American Journal of Psychiatry March 1, 2025
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nature Medicine July 24, 2025
- Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors. Molecular Pharmacology October 17, 2024
- The dopaminergic effects of esketamine are mediated by a dual mechanism involving glutamate and opioid receptors. Molecular Psychiatry February 19, 2025
and 21 more in the library
Cites 18
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
and 13 more in the library