Astrocytic μ-δ opioid receptor heterodimers mediate the antidepressant effects of ketamine’s metabolite
bioRxiv June 3, 2026 Shuo Yang, Ling-Jun Wang, Yunxiang Sun et al.
A 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.