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 DOI: 10.64898/2026.05.31.727553
Summary
AI-generated from the abstractA metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets μ-δ opioid receptor heterodimers on astrocytes. This interaction activates Gs-coupled signaling, increases intracellular cAMP, and elevates phosphorylated CREB levels and calcium dynamics in astrocytes, restoring key astrocytic proteins and functions in depression models. Disrupting the assembly of these opioid receptor heterodimers or Gs signaling eliminates HNK's antidepressant effects both in cells and in animals. The findings indicate that astrocytic opioid receptor heterodimers are critical for antidepressant responses and suggest HNK as a prototype for targeting astrocyte dysfunction in brain disorders.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Key finding | (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.