磷酸二酯酶2抑制剂Bay 60-7550对轻度睡眠不足抑郁模型小鼠持续术后疼痛的作用

Effect of Phosphodiesterase 2 Inhibitor Bay 60-7550 on Persistent Post-surgical Pain in Mice Model of Short-term Sleep Disturbance-induced Depression

目的探索磷酸二酯酶2抑制剂Bay60-7550对轻度睡眠不足抑郁模型小鼠持续术后疼痛的作用及可能机制。方法将实验小鼠分为假手术组、切口组、应激+假手术组、应激+切口组、应激+假手术+Bay 60-7550组和应激+切口+Bay60-7550;于术前1天,术后第1,4,7,9天进行机械痛阈值和热缩足潜伏期测试。行强迫游泳和糖水消耗试验评估小鼠抑郁样行为。检测各组小鼠血清皮质酮水平及脑内磷酸化环磷酸腺苷效应原件结合蛋白(phosphorylation cAMP-response element binding protein,pCREB)/CREB和脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)的表达。结果轻度睡眠不足使小鼠机械痛阈值从术后4 d开始明显下降,热痛潜伏期从术后7 d开始明显下降,持续到术后第9天,这些影响都可被Bay60-7550逆转。强迫游泳试验中,轻度睡眠不足导致小鼠不动时间明显增长,在糖水消耗试验中轻度睡眠不足导致小鼠术后第4天糖水消耗减少,但Bay60-7550能改善以上情况。手术与轻度睡眠不足均引起小鼠血清皮质酮升高,这种作用被Bay 60-7550逆转。持续术后疼痛与轻度睡眠不足均引起pCREB/CREB和BDNF蛋白表达减少。给予Bay 60-7550改善小鼠海马pCREB/CREB和BDNF表达。结论 PDE2抑制剂Bay 60-7550可改善轻度睡眠不足模型小鼠持续性术后疼痛情况,其机制可能与糖皮质激素相关的神经保护蛋白表达有关。

OBJECTIVE To explore the effect and mechanism of phosphodiesterase 2 inhibitor Bay 60-7550 on persistent post-surgical pain in mice model of short-term sleep disturbance-induced depression. METHODS The experimental mice were divided into sham operation group, incision group, stress+sham operation group, stress+incision group, stress+sham operation+Bay 60-7750 group and stress+incision+Bay 60-7750 group. Determination of paw withdrawl threshold and paw withdrawl latency were performed on one day before surgery, and 1, 4, 7, and 9 d after surgery, respectively. Assessment of depression-like behavior in mice was evaluated by forced swimming and sucrose preference test. The serum corticosterone levels and the expression of phosphorylation cAMP-response element binding protein(pCREB)/CREB and brain-derived neurotrophic factor(BDNF) in the hippocampus of each group of mice were measured. RESULTS Short-term sleep disturbance caused paw withdrawl threshold decreased significantly from 4 d after the operation, the latency period of heat pain decreased significantly from 7 d after the operation. At least these effects could be reversed by Bay 60-7550 until the 9 th day after operation. In the forced swimming experiment, short-term sleep disturbance caused the immobility time increased significantly, in the sugar and water consumption experiment, short-term sleep disturbance led to a decrease in sugar and water consumption on the 4 th day after surgery, Bay 60-7550 could improve the above situation. Both operation and short-term sleep disturbance caused an increase in serum corticosterone in mice, and this effect was reversed by Bay 60-7550. Both pCREB/CREB and BDNF protein expression were reduced in both surgery and short-term sleep disturbance. Bay 60-7550 was given to improve hippocampal pCREB/CREB and BDNF expression in mice. CONCLUSION PDE2 inhibitor Bay 60-7550 can improve persistent post-surgical pain in mice with short-term sleep disturbance. The mechanism may be related to the expression of glucocorticoid-related neuroprotective proteins.