The Zanos lab has just published a new study in the British Journal of Pharmacology demonstrating that the biologically-active metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK) shows potential for possibly addressing multiple aspects of opioid use disorder.

In this comprehensive investigation, we established several mouse models that mimic some of the human endophenotypes of opioid dependence and withdrawal. Our findings reveal that (2R,6R)-HNK effectively prevents conditioning to sub-effective doses of morphine in stress-susceptible mice and blocks conditioned place aversion induced by precipitated withdrawal in opioid-dependent mice.

Notably, a single administration of (2R,6R)-HNK reversed anhedonia, anxiety-like behaviors, and cognitive impairment that typically emerge during protracted opioid abstinence. The compound also facilitated extinction of opioid conditioning and prevented stress-induced reinstatement of drug-seeking behaviors.

Mechanistically, we found that (2R,6R)-HNK’s therapeutic effects involve restoration of impaired cortical high-frequency EEG oscillations through a GluN2A-NMDA receptor-dependent mechanism, addressing synaptic plasticity deficits induced by chronic opioid exposure and abstinence.

This research holds particular significance as (2R,6R)-HNK is currently advancing through Phase II clinical trials. The potential to repurpose this compound for addressing stress-related aspects of opioid use disorder could accelerate the development of much-needed new treatment options in the face of the ongoing opioid crisis.

The complete study, titled “(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice,” is now available in the British Journal of Pharmacology at:

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70018