Preoperative anxiety is common in patients undergoing elective surgery and is
closely related to postoperative hyperalgesia. In this study, a single prolonged
stress model was used to induce preoperative anxiety-like behavior in rats 24 h
before the surgery. We found that single prolonged stress exacerbated the
postoperative pain and elevated the level of serum corticosterone. Previous
studies have shown that glucocorticoid is associated with synaptic plasticity,
and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here,
single prolonged stress rats’ lumbar spinal cord showed reduced glutamic acid
decarboxylase-65, glutamic acid decarboxylase-67, GABA type A receptor alpha 1
subunit, and GABA type A receptor gamma 2 subunit, indicating an impairment of
GABAergic system. Furthermore, neuronal PAS domain protein 4 was also reduced in
rats after single prolonged stress 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 single prolonged
stress-induced hyperalgesia and reverse neuronal PAS domain protein 4 reduction
and the impairment of GABAergic system. Furthermore, overexpressing neuronal PAS
domain protein 4 could also restore the damage of GABAergic system caused by
single prolonged stress while interfering with neuronal PAS domain protein 4
caused an opposite effect. Finally, after stimulation of rat primary spinal cord
neurons with exogenous corticosterone in vitro, neuronal PAS domain protein 4
and GABAergic markers were also downregulated, 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 downregulation of neuronal PAS domain protein 4.