Sex dependence of opioid-mediated responses to subanesthetic ketamine
Tommaso Di Ianni, Matine M. Azadian, Sedona N. Ewbank, Michael Michaelides, Raag D. Airan
bioRxiv Preprint Server September 6, 2022 preprint DOI: 10.1101/2022.09.06.506854 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Rats |
| Interventions | Ketamine selective NMDAR antagonist |
| Topics | Esketamine Ketamine Addiction |
| Keywords | Rapid-acting antidepressant Sex differences Gender differences Male-female differences Sex-specific effects Sexual dimorphism Antidepressants Depression treatment Mood enhancers Psychiatric medication Neurobiology Brain research Neural pathways Brain mechanisms Neuropharmacology Opioid system Opioid signaling Opioid pathways Opioid receptors Opioid mechanism |
| Citations | 2 |
| Key findings | Ketamine's neurophysiologic, structural plasticity, and behavioral sensitization effects in rats depend on opioid signaling in a sex-dependent manner, with effects present in males but not females and reversed by gonadectomy. |
Abstract
Subanesthetic ketamine rapidly and robustly reduces depressive symptoms in patients with treatment-resistant depression. 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 ketamine in depression 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 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 opioid-mediated sex-dependent effects in ketamine-evoked structural plasticity and behavioral sensitization. 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.
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 |