The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement

Despite the thousands of lives lost during the ongoing opioid crisis, a scarcity of new and effective clinical treatments for opioid use disorder (OUD) remains. To address this unmet need, some researchers have turned to dissociative and psychedelic drugs to treat multiple psychiatric conditions. In particular, low doses of ketamine have been shown to attenuate opioid withdrawal and drug use in clinical and preclinical studies. However, ketamine has misuse liability and dissociative side effects that may limit its widespread application as a treatment for OUD. More recently, (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite that lacks misuse potential, has gained attention for its effectiveness in depression and stress models. To uncover its role in OUD, we tested the time-dependent effects of (2R,6R)-HNK on oxycodone withdrawal and reinstatement of oxycodone conditioned place preference (CPP). In male and female oxycodone-dependent mice, we found that 24h pretreatment with (2R,6R)-HNK (10 or 30mg/kg, s.c.) reduced the frequency of withdrawal-like behaviors and global withdrawal scores during naloxone-precipitated withdrawal, whereas 1h pretreatment with (2R,6R)-HNK only reduced paw tremors and the sum of global withdrawal scores but not GWS Z-scores. In other experiments, both 1h and 24h pretreatment with (2R,6R)-HNK (30mg/kg, s.c.) blocked drug-induced reinstatement of oxycodone CPP. Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.