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(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization

bioRxiv Wednesday 03 June 2026, 00:00 UTC By Liang, Y., Wang, L., Li, Y., Li, X., Sun, Y., Yang, M., Guo, X., Mu, J., Xu, C., Thapa, R., Cheng, Y., Zhang, H., He, Z., Yan, S., Yang, S., Fong, T. H., Bai, H., Xu, J., Zhang, Q., Lui, L., Li, M., Xu, D., Geng, W., Su, J., Tang, A., Wang, C., Zhou, Q., Cai, X. 1 min read
Key Points

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling.

Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both - and {delta}-opioid receptors in astrocytes. Chronic stress reduces -{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased -{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the -receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic -{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.
HNK (ORG) NMDAR (ORG) Astrocytic (ORG)
Originally published by bioRxiv Read original →

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