延胡索乙素分别与URB597和URB602联合应用对CCI大鼠镇痛作用的研究

<TITLE>ANALGESIC EFFECTS OF LEVO-TETRAHYDROPALMATINE COMBINED WITH URB597 OR URB602 RESPECTIVELY IN A RAT MODEL OF CHRONIC CONSTRICTION INJURY PAIN

目的：观察延胡索乙素（1evo—tetrahydropalmatine，L—THP）分别与脂肪酸酰胺水解酶（fatty acid amide hydrolase，FAAH）、单酰甘油脂肪酶（monoacylglycerol lipase，MAGL）特异性抑制剂URB597、URB602分别联合应用对坐骨神经慢性压迫损伤（chronic constriction injury，CCI）所致大鼠神经病理性疼痛的影响。方法：成年健康雄性Wistar大鼠30只，体重180～220g，随机分为5组（，z=6）：假手术组、CCI组、延胡索乙素CCI组、延胡索乙素URB597CCI组、延胡索乙素URB602CCI组。假手术组仅暴露坐骨神经但不结扎，其余组均暴露并结扎坐骨神经。术毕即刻，延胡索乙素CCI组、延胡索乙素URB597CCI组和延胡索乙素URB602CCI组腹腔注射延胡索乙素40mg／（kg·d），连续14d；假手术组和CCI组给予等量生理盐水。术后11d开始，延胡索乙素URB597CCI组、延胡索乙素URB602CCI组手术切口局部分别注射URB597、URB6020．3mg／（kg·d），连续4d，假手术组、CCI组、延胡索乙素CCI组注射等量生理盐水。于术前1d、术后3d、7d、11d、12d、13d、14d测试各组大鼠机械痛阈（mechanical withdrawal threshold，MWT）和热痛阈（thermal withdrawal latency，TwL）。结果：与术前和假手术组比较，CCI组、延胡索乙素CCI组、延胡索乙素URB597CCI组和延胡索乙素URB602CCI组大鼠，术后3d开始各时间点机械痛阈和热痛阈显著降低（P〈0．5）；与CCI组比较，延胡索乙素CCI组、延胡索乙素URB597CCI组和延胡索乙素URB602CCI组大鼠术后3d、7d、11d、12d、13d、14d机械痛阈和热痛阈显著提高（P〈0．05）；与延胡索乙素CCI组比较，延胡索乙素URB597CCI组、延胡索乙素URB602CCI组大鼠，术后11d、12d、13d、14d机械痛阈和热痛阈明显提高（P〈0．05）；与延胡索乙素URB597CCI组比较，延胡索乙素URB602CCI组大鼠各时间点机械痛阈和热痛阈无显著性差异（P〉O．05）。结论：在CCI大鼠模型中，延胡索乙素可以产生良好的镇痛作用，当分别与URB597、URB602合用时可以增强其镇痛作用。

Objective： To observe the effects of levo-tetrahydropalmatine （L-THP） combined with URB597 or URB602 [specific inhibitors of fatty acid amide hydrolase （FAAH） or monoacylglycerol lipase （MAGL）], on a rat CCI model of neuropathic pain. Methods： Thirty male Wistar rats weighing 180-220 g were randomly divided into 5 groups （n = 6）： sham group, CCI group, L-THP CCI group, L-THP ＋ URB597 CCI group and L-THP ＋ URB602 CCI group. Rats in L-THP CCI group, L-THP ＋ URB597 CCI group and L-THP ＋ URB602 CCI group were administrated with L-THP 40 mg/（kg · d） intraperitoneally for 14 days continuously after the CCI surgery. In both sham and CCI groups, rats were given isometric normal saline. Starting from the 1 lth day after surgery, rats in groups L-THP ＋ URB597 CCI and L-THP ＋ URB602 CCI were administrated with URB597 or URB602 0.3 mg/（kg · d） respectively in the local incision of right hind leg, once a day for 4 days. Meanwhile, rats in Sham, chronic constriction injury L-THPCCI groups were injected with normal saline. Mechanical withdrawal threshold （MWT） were tested using von Frey filaments and controlled infrared noxious radiant heat stimulus for thermal withdrawal latency （TWL） on the day before surgery and 3 d, 7 d, 11 d, 12 d, 13 d and 14 d after surgery. Results： Compared with before surgery and sham groups, MWT and TWL were decreased after surgery in CCI, L-THP CCI, L-THP ＋ URB597 CCI and L-THP ＋ URB602 CCI groups （P 〈 0.05）. Compared with CCI group, MWT and TWL were increased significantly at 3 d, 7 d, 11 d, 12 d, 13 d and 14 d after surgery in groups L-THP CCI, L-THP ＋ URB597 CCI and L-THP ＋ URB602 CCI （P 〈 0.05）. Compared with L-THP CCI group, MWT and TWL were increased at 11 d, 12 d, 13 d, 14 d after surgery in groups of L-THP ＋ URB597 CCI and L-THP ＋ URB602 CCI （P 〈 0.05）. No significant difference was found between L-THP ＋ URB597 CCI and L-THP ＋ URB602 CCI groups （P 〉 0.05）. Conclusion： Enhanced effects were observed when combining L-THP with URB597 or URB602 compared to L-THP alone in rat CCI model of neuropathic pain. This may provide a new approach for exploring mechanisms and therapeutic methods of neuropathic pain.