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.