Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine’s metabolite
Shuo Yang, Ling-Jun Wang, Yunxiang Sun, Xiaoyan Ma, Yi Rong, Fong Tsz Hei, Tianxiang Li, Di Deng, Xiao-Xue Li, Zhaoxiang Zhang, Yan-Xia Liang, Xianzhang Bu, Tao Peng, Huan Xu, Chuang Wang, Xiang Cai, Qiang Zhou
bioRxiv June 3, 2026 preprint DOI: 10.64898/2026.05.31.727553 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Topics | Esketamine Ketamine |
| Key findings | (2R,6R)-hydroxynorketamine (HNK) selectively targets μ-δ opioid receptor heterodimers on astrocytes to produce antidepressant effects through Gs-coupled signaling. |
Abstract
Abstract A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamine’s antidepressant efficacy, yet their precise contributions remain poorly understood. Here, we demonstrate that one major metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets μ-δ opioid receptor heterodimers (μ-δ-ORs) on astrocytes. By promoting the formation and/or stabilization of μ-δ-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca²⁺ dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting μ-δ-OR assembly or Gs signaling abolishes HNK-mediated antidepressant responses both in vitro and in vivo. Collectively, astrocytic opioid receptor heterodimers are critical to antidepressant responses and HNK may serve as a prototype compound for targeting astrocyte dysfunction across a wide range of brain disorders.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| S(+)-ketamine Effect on Experimental Pain and Cardiac Output Healthy adult volunteers (10 men and 10 women) | 2009 | Pharmacokinetic-pharmacodynamic modeling study in healthy volunteers | n = 20 |
Citations in the library
Cites 23
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018
- 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
and 18 more in the library