S-Ketamine Alleviates Anxiety-Induced Chronic Postoperative Pain by Affecting Glucose Metabolism of Striatal Microglia in a Rat Model.

Abstract

Patients admitted for surgery commonly experience preoperative anxiety. Previous studies have shown that preoperative anxiety often delays recovery from postoperative pain or even aggravates pain. Therefore, it is necessary to explore the mechanisms by which anxiety prolongs chronic postoperative pain. A single prolonged stress (SPS) rat model was constructed to investigate the effects of anxiety and depression using behavioral tests. Changes in the levels of tight junction proteins in the cerebral striatum (CPu) of the rats were assessed by western blotting 1 to 21 days after the operation. The level of inflammation was detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Glucose metabolism levels and changes in related signaling pathways in microglia were assessed using western blotting, immunofluorescence, ELISA, and flow cytometry. The effects of S-ketamine treatment on the rats were also determined using the above methods. Preoperative SPS aggravated acute pain after plantar incision in rats and significantly prolonged the postoperative pain recovery time. The incised SPS rats began to show significant blood-brain-barrier (BBB) damage on the third day after surgery. Simultaneously, SPS caused neuroinflammation and microglial activation in the CPu after plantar incision. CPu microglia participated in neuroinflammation by undergoing glucose metabolic reprogramming mediated by the mTOR-p70S6K-4EBP1 pathway. Preoperative administration of a single dose of S-ketamine was an effective analgesic, as it inhibited SPS-induced postoperative inflammation. S-ketamine partially corrected SPS-induced abnormal glycolysis in striatal microglia through the mTOR-p70S6K-4EBP1 pathway. S-ketamine effectively relieved postoperative chronic pain caused by preoperative anxiety by correcting glucose metabolic reprogramming in CPu microglia.