(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic µ-δ opioid receptor heterodimerization
Yanxia Liang, Lingjun Wang, Yajie Li, Xiaoxue Li, Yunxiang Sun, Mengli Yang, Xu Guo, Junxu Mu, Chang Xu, Rupak Thapa, Ye Cheng, Huiqiang Zhang, Zecong He, Shi Yan, Shuo Yang, T. Fong, Huiyuan Bai, Jia Xu, Qi Zhang, Lui Lei, Ming Li, Dongwu Xu, Wujun Geng, Jianzhong Su, Ai-Hui Tang, Chuan Wang, Qiang Zhou, Xiang Cai
bioRxiv June 3, 2026 preprint DOI: 10.64898/2026.05.31.729044 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study |
|---|---|
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Key findings | HNK potentiates hippocampal excitatory transmission and reverses stress-induced behavioral deficits through astrocytic mu- and delta-opioid receptor heterodimers; chronic stress reduces these heterodimers, and a single HNK dose restores their abundance. Mutating Asp147 and Tyr148 on the mu-receptor abolishes HNK-driven heterodimer formation and its rapid antidepressant-like effects. |
Abstract
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 µ- and δ-opioid receptors in astrocytes. Chronic stress reduces µ-δ receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased µ-δ heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the µ-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic µ-δ opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.