Lack of Beneficial Effect for Preemptive Analgesia in Postoperative Pain Control: Verifying the Efficacy of Preemptive Analgesia with N-Methyl-D-Aspartate Receptor Antagonists in a Modified Animal Model of Postoperative Pain
Lack of Beneficial Effect for Preemptive Analgesia in Postoperative Pain Control: Verifying the Efficacy of Preemptive Analgesia with N-Methyl-D-Aspartate Receptor Antagonists in a Modified Animal Model of Postoperative Pain
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DOI：
10.1213/ane.0b013e318207c504
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发表时间：
2011-03-01
影响因子：
5.7
通讯作者：
Chu, Ya-Chun
中科院分区：
文献类型：
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作者：
Chang, Wen-Kuei;Tao, Yuan-Xiang;Chu, Ya-Chun
背景技术背景：在先前的动物研究中，用N-甲基-D-天冬氨酸（NMDA）拮抗剂预先治疗在预防切口诱导的异常性疼痛方面无效。该模型很可能与测试术后疼痛的治疗效果无关。只有通过在特定疼痛类型或动物模型中证实有效的治疗，才能验证抢先治疗的有益效果。我们以前表明，NMDA受体拮抗剂有效地减轻增强机械性痛觉过敏后，足底切口在成年大鼠，已给予角叉菜胶作为新生儿足底注射。在这里，使用这种改进的模型，我们测试了预先用NMDA拮抗剂MK-801治疗的效果。方法：在出生后第1天，在大鼠的一只后爪足底表面皮下注射0.25%角叉菜胶或生理盐水。在出生后第50天，处死大鼠，并收获腰脊髓的同侧，用于在基线、足底切口后2小时、4小时、8小时和24小时（每个时间点每组n = 5）的NR 2A和NR 2B表达的生化分析。对于药理学研究，将大鼠分配至以下组之一：足底切开前15分钟鞘内注射1次40 nmol MK-801，足底切开后30分钟鞘内注射1次，或在足底切开后15分钟和60分钟注射2次20 nmol或40 nmol（对于生理盐水处理的大鼠，每组n = 10，对于角叉菜胶处理的大鼠，每组n = 12）。结果：角叉菜胶处理组大鼠足跖切口后4 h，NMDA受体亚单位NR 2A和NR 2B的表达显著高于生理盐水处理组，且NR 2A和NR 2B的表达均显著高于生理盐水处理组。疼痛敏感性试验显示MK-801可显著减轻角叉菜胶所致的机械性痛敏，提高大鼠损伤足爪的负重率。然而，根据术后6小时观察期的评估，术前治疗并不上级于术后治疗。术后连续注射2次的组表现出延长的镇痛作用。只有接受2术后注射和增加总剂量的组有改善的镇痛index.Conclusions：证明的NMDA拮抗剂的镇痛作用的条件下，我们表明，preincisional治疗是不是更有益于postincisional治疗术后疼痛缓解在修改后的动物模型。与单次注射相比，增加给药持续时间和/或总剂量具有递增的镇痛作用。（Anesth Analg 2011;112：710-8）
BACKGROUND: In previous animal studies, preemptive treatments with N-methyl-D-aspartate (NMDA) antagonists were ineffective at preventing incision-induced allodynia. It is very likely that the model was not clinically relevant for testing treatment effects on postoperative pain. The beneficial effects of preemptive treatment can be verified only by treatments with a pharmacologically proven effect in a specific pain type or animal model. We previously showed that NMDA receptor antagonists effectively alleviate enhanced mechanical hyperalgesia after plantar incision in adult rats that had been given an intraplantar injection of carrageenan as neonates. Here, using this modified model, we tested the efficacy of preemptive treatment with the NMDA antagonist MK-801.METHODS: We injected rat pups subcutaneously with 0.25% carrageenan or saline in the plantar surface of one hindpaw on postnatal day 1. On postnatal day 50, rats were killed and the ipsilateral side of the lumbar spinal cords were harvested for biochemical analysis of the expression of NR2A and NR2B at baseline, 2 hours, 4 hours, 8 hours, and 24 hours after plantar incision (n = 5 per group for each time point). For pharmacological study, rats were allocated into one of the following groups: 1 intrathecal injection of 40 nmol MK-801 15 minutes before plantar incision, 1 intrathecal injection 30 minutes after plantar incision, or 2 injections of 20 nmol or 40 nmol given at 15 minutes and 60 minutes after plantar incision (n = 10 per group for neonatally saline-treated and 12 for carrageenan-treated rats). Paw withdrawal thresholds were measured with von Frey filaments, and weight-bearing percentages were measured hourly after plantar incision.RESULTS: Expressions of NMDA receptor subunits NR2A and NR2B were increased maximally 4 hours postoperatively and were significantly greater in carrageenan-treated rats than in saline-treated rats. Tests of pain sensitivity showed that MK-801 significantly alleviated the incision-induced mechanical hyperalgesia and increased weight-bearing percentage on the injured paw in carrageenan-treated rats. However, preincisional treatment was not superior to postincisional treatment as assessed during the 6-hour postoperative observation period. Groups with 2 successive postoperative injections exhibited prolonged analgesic effects. Only the group that received 2 postoperative injections and increased total dosage had improved analgesic indices.CONCLUSIONS: Under conditions of proven analgesic action of an NMDA antagonist, we demonstrated that preincisional treatment is not more beneficial than postincisional treatment for postoperative pain relief in the modified animal model. Increasing the duration of administration and/or total dosage had an incremental analgesic effect in comparison with a single injection. (Anesth Analg 2011;112:710-8)