Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats
Tommaso Di Ianni, Sedona N. Ewbank, Marjorie R. Levinstein, Matine M. Azadian, Reece C Budinich, Michael Michaelides, Raag D. Airan
Nature Communications January 30, 2024 DOI: 10.1038/s41467-024-45157-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Subanesthetic ketamine |
| Measures | pharmacological functional ultrasound imaging, postsynaptic density, behavioral sensitization, opioid receptor density |
| Topics | Addiction Esketamine Ketamine |
| Key findings | Blocking opioid receptors suppressed neurophysiologic changes evoked by subanesthetic ketamine, but not by a more selective NMDA receptor antagonist, in limbic regions. This opioid-dependent response was evident in males but not females and was reversed by surgical removal of the male gonads. Similar sex-dependent opioid effects were observed for ketamine-evoked postsynaptic density, behavioral sensitization, and opioid receptor density. |
Abstract
Subanesthetic ketamine is increasingly used for the treatment of varied psychiatric conditions, both on- and off-label. While it is commonly classified as an N -methyl D-aspartate receptor (NMDAR) antagonist, our picture of ketamine’s mechanistic underpinnings is incomplete. Recent clinical evidence has indicated, controversially, that a component of the efficacy of subanesthetic ketamine may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that blocking opioid receptors suppressed neurophysiologic changes evoked by ketamine, but not by a more selective NMDAR antagonist, in limbic regions implicated in the pathophysiology of depression and in reward processing. Importantly, this opioid-dependent response was strongly sex-dependent, as it was not evident in female subjects and was fully reversed by surgical removal of the male gonads. We observed similar sex-dependent effects of opioid blockade affecting ketamine-evoked postsynaptic density and behavioral sensitization, as well as in opioid blockade-induced changes in opioid receptor density. Together, these results underscore the potential for ketamine to induce its affective responses via opioid signaling, and indicate that this opioid dependence may be strongly influenced by subject sex. These factors should be more directly assessed in future clinical trials. In rats, functional ultrasound imaging reveals that blocking opioid receptors modulates the effects of subanesthetic ketamine on neural activity in males but not in females, with parallel changes in ketamine’s effects on brain structure and behavior.
Comparable studies
Other preclinical and animal studies on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder. Morphine-dependent rats and mice | 2020 | Preclinical study | |
| The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement. Male and female oxycodone-dependent mice | 2023 | Preclinical study | |
| Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile. Adolescent rats of both sexes, including naïve and early-life stressed (maternal... | 2025 | Preclinical study | |
| Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats. Long Evans rats | 2024 | Preclinical experimental study | |
| Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way. Male and female mice with forebrain ASM overexpression | 2025 | Experimental study |