Papers of the Week

Preoperative anxiety is common in patients undergoing elective surgery and is closely related to postoperative hyperalgesia. In this study, a single prolonged stress (SPS) model was used to induce preoperative anxiety-like behavior in rats 24h before the surgery. We found that SPS exacerbated the postoperative pain and elevated the level of serum corticosterone (CORT). Previous studies have shown that glucocorticoid (GC) is associated with synaptic plasticity, and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here, SPS rats lumbar spinal cord showed reduced glutamic acid decarboxylase-65 (GAD65), glutamic acid decarboxylase-67 (GAD67), GABA type A receptor alpha 1 subunit (GABAA α1), and GABA type A receptor gamma 2 subunit (GABAA γ2) , indicating an impairment of GABAergic system. Furthermore, Neuronal PAS domain protein 4 (Npas4) was also reduced in rats after SPS stimulation, which has been reported to promote GABAergic synapse development. Then intraperitoneal injection of RU486 (a glucocorticoid receptor antagonist) rather than spironolactone (a mineralocorticoid receptor antagonist) was found to relieve SPS induced hyperalgesia and reverse Npas4 reduction and the impairment of GABAergic system. Further over-expressing Npas4 could also restore the damage of GABAergic system caused by SPS while interfering with Npas4 caused an opposite effect. Finally, after stimulation of rat primary spinal cord neurons with exogenous CORT in vitro, Npas4 and GABAergic markers were also down-regulated, and RU486 reversed that. Together, our results demonstrated that preoperative anxiety led to GABAergic system impairment in spinal cord and thus caused hyperalgesia due to glucocorticoid-induced down-regulation of Npas4.