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

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.

doi:10.64898/2026.05.31.727553

bioRxiv · 10.64898/2026.05.31.727553

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

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.

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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 ketamines antidepressant efficacy, yet their precise contributions remain poorly understood. Here, we demonstrate that one major metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), selectively targets -{delta} opioid receptor heterodimers (-{delta}-ORs) on astrocytes. By promoting the formation and/or stabilization of -{delta}-ORs, HNK engages Gs-coupled signaling, elevates intracellular cAMP, phosphorylates CREB (p-CREB) levels and Ca{superscript 2} dynamics in astrocytes, and consequently restores key astrocytic proteins and functions in depression models. Disrupting -{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.

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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.. 2026-06-03. Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine's metabolite. https://doi.org/10.64898/2026.05.31.727553

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