TET1 downregulation in the dorsal root ganglion and spinal cord is required for short-term sleep disturbance to delay surgical pain recovery

BACKGROUND: Sleep disturbance delays surgical pain recovery. This impact is associated with gene dysregulation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH). However, the mechanisms underlying this dysregulation remain unclear. METHODS: Expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) was examined in the DRG and SDH following plantar incision in rats subjected to short-term rapid eye movement sleep disturbance. A herpes simplex virus expressing Tet1 mRNA (HSV-TET1) was microinjected into the ipsilateral L4 and L5 DRGs or SDH, and its effects on μ-opioid receptor (MOR) expression, TET1 binding to the Oprm1 promoter, and promoter-associated 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in microinjected regions were assessed. Pain behaviours were evaluated, and the effect of Tet1 siRNA microinjection, with or without a lentivirus expressing Oprm1 mRNA (LV-MOR), on MOR expression in microinjected DRGs and SDH and nociceptive threshold in naïve rats was assessed. RESULTS: Short-term rapid eye movement sleep disturbance downregulated TET1 in the ipsilateral L4 and L5 DRGs and SDH and prolonged incisional pain. HSV-TET1 microinjection restored MOR expression, TET1 binding activity to the Oprm1 promoter, and 5hmC levels at the promoter, while reducing 5mC accumulation, in microinjected L4 and L5 DRGs or SDH and prevented short-term rapid eye movement sleep disturbance-induced prolongation of incisional pain. Conversely, Tet1 siRNA microinjection reduced MOR expression in microinjected L4 and L5 DRGs or SDH and induced nociceptive hypersensitivity, effects abolished by LV-MOR co-microinjection. CONCLUSIONS: TET1 downregulation is required for short-term sleep disturbance to delay surgical pain recovery, likely by reducing μ-opioid receptor expression in the dorsal root ganglion and spinal dorsal horn.