( 2R,6R )-hydroxynorketamine facilitates extinction and prevents emotional impairment and stress-induced reinstatement in morphine abstinent mice

ABSTRACT Opioid addiction is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states and anhedonia-driven behaviors. In addition to the current epidemic that was declared in the U.S.A., opioid-related deaths are increasing in other countries around the world. Classical antidepressants, or the currently prescribed opioid substitution pharmacotherapies have limited efficacy to reverse maladaptive behavioral responses, negative affect or prevent relapse in opioid abstinent individuals. Here, by establishing and using novel mouse models for the study of opioid addiction, we demonstrate, for the first time, the therapeutic potential of ketamine’s metabolite, ( 2R,6R )-hydroxynorketamine (HNK). In particular, our studies showcase ( 2R,6R )-HNK’s ability to reverse conditioning to sub-effective doses of morphine in stress-susceptible mice, prevent conditioned-place aversion and mitigate acute somatic withdrawal symptoms in opioid-dependent animals. In addition, we show that this metabolite reverses anhedonia, anxiety-like behaviors, cognitive impairment, and general stress susceptibility associated with protracted opioid withdrawal, thereby presenting a promising therapeutic avenue for opioid relapse prevention. Our results strongly suggest that ( 2R,6R )-HNK, potentially by augmenting downstream brain-derived neurotrophic factor (BDNF) and GluN2A N -methyl-D-aspartate receptor signaling, effectively reverses maladaptive behavioral responses typical of protracted opioid abstinence. Furthermore, it facilitates the extinction of opioid conditioning and prevents stress-induced reinstatement of opioid-seeking behaviors. Our findings highlight how ( 2R,6R )-HNK, through an enhancement of synaptic plasticity in mood-regulating brain areas, has the potential to be an effective, next-generation pharmacotherapy for opioid use disorders by addressing emotional disturbances associated with protracted abstinence. SIGNIFICANCE STATEMENT Our studies represent a comprehensive exploration into the critical facets of opioid addiction and abstinence, offering critical insights into the significant potential of ( 2R,6R )-HNK as a treatment for this disorder. By unraveling the complex dynamics of opioid withdrawal and addressing the profound emotional disturbances underlying relapse vulnerability, our findings illuminate a promising innovative avenue for therapeutic intervention. The demonstrated ability of ( 2R,6R )-HNK to reverse maladaptive behaviors emerging during protracted opioid abstinence, facilitate extinction of opioid conditioning, prevent stress-induced reinstatement, represents a paradigm shift in addiction research. These revelations not only deepen our comprehension of the neurobehavioral complexities associated with opioid abstinence but also underscore the profound implications of ( 2R,6R )-HNK as a prospective pharmacotherapy in mitigating the devastating impact of opioid use disorder, potentially transforming addiction treatment strategies.