米氮平对奥沙利铂诱导大鼠神经病理性疼痛及脊髓NMDAR-2B表达的影响

Effects of mirtazapine on the oxaliplatin-induced neuropathic pain and spinal NR2Bexpression in rats

目的探讨米氮平对奥沙利铂引起的神经病理性疼痛的疗效及可能机制。方法 40只SD大鼠随机均分为葡萄糖+吐温80(C组)、奥沙利铂+吐温80(O组)、奥沙利铂+米氮平10mg/kg组(M1组)、奥沙利铂+米氮平20mg/kg组(M2组)和奥沙利铂+米氮平30mg/kg组(M3组)。每天分别给予大鼠口服吐温80和米氮平10、20、30mg/kg,28d后测各组大鼠的热刺激缩足潜伏期(TWL)和机械性缩足阈值(MWT)。然后重新选取32只SD大鼠,随机均分为葡萄糖+生理盐水+吐温80(C组)、奥沙利铂+生理盐水+吐温80(O组)、奥沙利铂+生理盐水+米氮平20mg/kg(M组)和奥沙利铂+WAY100635+米氮平20mg/kg(W组)。W组在给予米氮平灌胃前30min腹腔注射1mg/kgWAY100635,连续应用28d后测各组大鼠的MWT。同时应用westernblot检测脊髓N-甲基-D-天冬氨酸受体2B(NMDAR-2B)即NR2B的表达。结果在冷水缩尾测试中,其他四组大鼠的TWL在第3天和第10、17、24天明显低于C组(P<0.05或P<0.01)。奥沙利铂注射后第7、14、21、28天,O组大鼠MWT明显低于C组(P<0.05)。治疗后第14、21、28天,M2和M3组大鼠MWT明显高于O组(P<0.05)。预先给予WAY100635,在奥沙利铂注射后第14、21、28天,W组大鼠MWT明显低于M组(P<0.05)。O组脊髓水平NR2B表达明显高于C组(P<0.05),M2和M3组明显低于O组(P<0.05)。预先给予WAY100635,W组脊髓水平NR2B表达明显高于M组(P<0.05)。结论奥沙利铂引起的触觉痛觉异常与脊髓NR2B表达增高有关,米氮平可能通过5-HT1A受体减轻触觉痛觉异常和上调NR2B表达;但米氮平对冷痛觉过敏无明显改善。

Objective To investigate the effects of mirtazapine on the oxaliplatin-induced neuropathy in rats as well as the underlying mechanism. Methods Forty male SD rats were randomly devided into 5 groups： control group （group C）, model group （group O） and three mirtazapine therapeutic groups （groups M1, M2 and M3）. Animals in each group received vehicle or mirtazapine 10, 20, and 30 mg-kg 1. day 1 per-orally respectively for 28 consecutive days. Subsequently, another thirty-two animals were randomly devided into 4 groups., control group （group C）, model group （group O）, mirtazapine 20 mg/kg group （group M） and WAY100635 pretreatment group （group W）. In group W, 1 mg/kg of WAY100635 was preadministrated 30 rain before mirtazapine 20 mg. kg-1 .day-1. TWL and MWL were measured as behavioral testing. The expression of NMDA receptor subunit NR2B in lumbar segment of spinal cord was determined by western blot. Results Compared with group C, TWL in other four groups decreased significantly on day 3 （P〈0.05） and day 10, 17, 24 （P%0.01）, MWT in group O decreased from day ？ to 28 （P%0. 05）. MWT were increased in group M2 and M3 compared to group O on day 14, 21, 28 （P%0.05）. Compared with group M, MWT in group W decreased significantly on day 14, 21, 28 （P〈0.05）. The expression of NR2B increased in group O compared with group C （P%0.05）, decreased in group M2 and Ma compared with group O （P〈 0.05）, increased in group W compared with group M （P〈 0.05）. Conclusion Oxaliplatin-induced mechanical allodynia is associated with spinal NRgB up-regulation,which may be attenuated by mirtazapine administration via 5-HTIA receptor. But mirtazapine shows no effect on cold hyperalgesia.