(2R,6R)-Hydroxynorketamine restores postsynaptic localization of AMPAR in the prelimbic cortex to provide sustained pain relief

Abstract Neuropathic pain is a difficult-to-treat pain condition that can affect patients for years. (2R,6R)-hydroxynorketamine (R-HNK) is a ketamine metabolite without dissociative effects and has been evaluated as an alternative to ketamine in chronic pain management. The mechanism of action remains elusive. Here we report that repeated systemic or contra-prelimbic cortex (PrL) infusion of R-HNK in the acute stage of nerve injury produces sustained pain relief for at least 14 days in the mouse spared nerve injury (SNI) model of neuropathic pain. Transcriptomic analysis suggests that SNI is associated with increased Brain-derived neurotrophic factor (Bdnf) signaling, abnormal dendritic spine organization, and reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in PrL. Activity-regulated cytoskeleton-associated protein (Arc) is identified as the top gene in the leading-edge analysis of the gene set. R-HNK administration abolishes these transcriptomic changes. Further studies confirm the transcriptome findings. Finally, we show that enhancing PrL activity by R-HNK increases PrL-periaqueductal gray (PAG) connectivity, which is essential for R-HNK-mediated pain relief. Our study highlights AMPAR suppression due to continuous Bdnf/Arc elevation in PrL as a mechanism of central sensitization after SNI. R-HNK can recalibrate Bdnf/Arc/AMPAR axis and restore PrL-PAG connectivity to induce sustained alleviation of neuropathic pain.