帕罗西汀对神经病理性疼痛模型小鼠镇痛作用的实验研究

Experimental study in the analgesic effects of paroxetine on the mice model of neuropathic pain

目的观察新型抗抑郁药帕罗西汀对慢性压迫性损伤（chronicconstrictioninjury，CCI）疼痛模型小鼠的镇痛作用，并探讨该作用与海马CA1区脑源性神经营养因子（brain-derivedneurotrophicfactor，BDNF）表达变化的关系。方法雄性健康小鼠48只，采用随机数字表法分为假手术组（Sham组）和CCI模型组（CCI组），每组24只。两组小鼠于术后第3天开始分别给予帕罗西汀（20mg·kg-1．d-1）或等量生理盐水（NS）灌胃，连续给药7d，从第8天开始停止给药，再分为Sham＋P组、sham＋Ns组、CCI＋P组、CCI＋NS组，每组12只。①于CCI模型建立后第0、3天，以及给药后第1、3、7、8、9、10、11天分别检测实验小鼠的热缩足潜伏期（pawwithdrawallatency，PwL）变化。②将CCI＋P组、CCI＋NS组实验动物按随机数字表法随机分成CCI＋P＋BDNF组、CCI＋P＋磷酸盐缓冲液（phosphatebufferedsaline，PBS）组、CCI＋NS＋BDNF组、CCI＋NS＋PBS组，每组6只，帕罗西汀给药7d后于CCI对侧海马CA1区注射小剂量外源性BDNF（5ng／0．2μl），观察BDNF注射后1、2、4h小鼠的PwL变化。结果与Sham＋NS组比较，Sham＋P组小鼠灌胃后各时间点PWL无明显变化（P〉0．05）；灌胃后第3、7天和停药第1天CCI＋P组小鼠PwL分别为（6．66±0．35）、（8．36±0．33）S和（7．84±0．37）S，较CCI＋NS组（5．01±0．24）、（5．58±0．40）、（6．24±0．35）s明显升高（P〈0．01、P〈0．001或P〈0．05）；然而，停药第2天CCI＋P组小鼠PWL与CCI＋NS组比较，差异无统计学意义（P〉0．05）；与CCI＋NS＋PBS组比较，CCI＋NS＋BDNF组在各时间点PWL差异均无统计学意义（P〉0．05）；注药后1、2h和4h，CCI＋P＋BDNF组小鼠PWL分别为（5．78±0．39）、（5．34±0．47）S和（5．85±1．13）S，较CCI＋P＋PBS组（8．96±0．54）、（8．99±0．99）、（9．43±0．70）s明显降低（P〈0．01或P〈0．05）。结论新型抗抑郁药帕罗西汀对神经病理性疼痛CCI模型小鼠有确切的镇痛效果，该作用与其调控海马BDNF表达有关。

Objective To investigate the analgesic effect of the novel antidepressant drug paroxetine on the mice neuropathic pain induced by chronic constriction injury（CCI）, and explore the relation between the analgesic effect of paroxetine and the change of brain-derived neurotrophic factor （BDNF） expression in hippocampal CA1 region. Methods Forty eight healthy male mice were randomly divided into two groups using the random number table method： Sham group and CCI group. From postoperative 3 d, the mices in two groups were orally given paroxetine or saline for 7 d. The drug administration was stopped on eighth day and then the mices were further divided into Sham＋P group, Sham＋NS group, CCI＋P group and CCI＋NS group （ 12 mices in each group. The paw withdrawal latency （PWL） was measured on 0 d and 3 d after the operation and 1, 3, 7, 8, 9, 10 d, and 11 d after drug administration, respectively. The animal in the CCI＋P and CCI＋NS groups were randomly divided into CCI＋P＋BDNF group, CCI＋P＋PBS group, CCI＋NS＋BDNF group and CCI＋NS＋PBS group （6 rats in each group）. After 7 d of paroxetine treatment, small dose of exogenous BDNF was injected into contralateral hippocampus CA1 region in the CCI mices. Results Compared with Sham＋NS group, the PWL at each time point after drug administration did not statistically differ in the Sham＋P group （P〉0.05）. Compared with CCI＋NS group（5.01±0.24）, （5.58±0.40）, （6.24±0.35） s, the PWL was significantly increased at 3 d and 7 d afterdrug administration [（6.66±0.35） s and （8.36±0.33） s] and at 1 d after drug discontinuation [（7.84±0.37） s] in the CCI＋P group （P〈0.01, P〈0.01 and P〈0.05）. The PWL at 2 d after drug discontinuation was not statistically significant between the CCI＋P and CCI＋NS groups. Compared with the CCI＋NS＋PBS group, the PWL at each time point was not statistically difference in the CCI＋NS＋ BDNF group（P〉0.05）. Compared with the CCI＋P＋PBS group （8.96±0.54）, （8.99±0.99）, （9.43±0.70） s, the PWL at 1, 2 h and 4 h after drug administration were significantly decreased in the CCI＋P＋BDNF group [ （5.78±0.39）, （5.34±0.47） s and （5.85± 1.13 ） s, P〈0.001 or P〈0.05 ）]. Conclusions The novel antidepressant paroxetine can produce significant analgesic effect on CCI-induced neuropathie pain and its analgesic effect are related to regulation of expression of BDNF in hippoeampal CA1 region.