Ketamine Modulates Endogenous Opioid Peptide Signaling and Reduces Heroin-Seeking in Male Long-Evans Rats
Adam Dawoud, Achla Gupta, Ivone Gomes, Dylan Baker, Julia E Shapiro, Lakshmi A Devi, Yasmin L. Hurd, Aya Osman
bioRxiv (Cold Spring Harbor Laboratory) September 6, 2026 preprint DOI: 10.64898/2026.09.01.748554 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Population | Male Long-Evans rats |
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine increased endogenous opioid gene and peptide expression, mu-opioid receptor protein, and G protein activity, particularly in the nucleus accumbens shell, and altered NMDAR subunit expression. It significantly reduced heroin-primed but not cue-induced seeking, suggesting reduced acute relapse vulnerability. |
Abstract
Opioid Use Disorder (OUD) continues to be a pressing public health crisis, marked by high relapse rates and limited treatment options. Ketamine, a non-competitive N-Methyl-D-Aspartate receptor (NMDAR) antagonist, has emerged as a promising therapeutic for numerous psychiatric illnesses due to its robust antidepressant properties and glutamate-mediated synaptic plasticity. However, ketamine's therapeutic mechanisms remain elusive, with emerging evidence implicating the endogenous opioid system. Furthermore, few studies have investigated ketamine's potential as an intervention for OUD. Accordingly, this study assessed ketamine's ability to rewire endogenous opioid and glutamatergic circuitry and reduce heroin-seeking activity in male Long-Evans rats. Using a multi-cohort design, we investigated ketamine's effects on opioid-related transcriptional, protein, and signaling properties in key brain regions associated with reward and addiction, and subsequently on heroin-seeking using a self-administration paradigm. To investigate mechanisms of plasticity, we also quantified transcriptional changes to NMDAR subunits. Molecular analyses demonstrated increased expression of endogenous opioid system-related genes and endogenous opioid peptides at the protein level, elevated mu-opioid receptor protein levels, and enhanced G protein activity, suggesting increased receptor function. Notably, transcriptional changes were particularly prominent in the shell subregion of the nucleus accumbens (NAc). We also revealed that ketamine altered NMDAR subunit expression in the medial prefrontal cortex and NAc, indicating circuit-level synaptic remodeling. Behavioral analyses revealed that ketamine significantly reduced heroin-primed, but not cue-induced, seeking activity. Together, these findings suggest ketamine reduces acute relapse vulnerability to opioids through coordinated modulation of opioid and glutamatergic systems, highlighting its potential as a novel intervention for OUD.
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
Cites 13
- 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
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of Substance Abuse Treatment December 1, 2002
- Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence Journal of Psychoactive Drugs March 1, 2007
and 8 more in the library