Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine's metabolite

Authors

Yang, S., Wang, L. J., Sun, Y., Ma, X., Rong, Y., Fong, T. H., Li, T., Deng, D., Li, X.-X., Zhang, Z., Liang, Y.-X., Bu, X., Peng, T., Xu, H., Wang, C., Cai, X., zhou, q.

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 mu-delta opioid receptor heterodimers ( mu-delta-ORs) on astrocytes. By promoting the formation and/or stabilization of mu-delta-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca 2+ dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting mu-delta-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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Jun 2026.

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