Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine
Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine
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DOI：
10.1097/00000542-199809000-00023
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发表时间：
1998-09-01
期刊：
影响因子：
8.8
通讯作者：
Weber, E
中科院分区：
文献类型：
--
作者：
Nishiyama, T;Yaksh, TL;Weber, E
背景：N-甲基-D-天冬氨酸（NDMA）拮抗剂对急性伤害性感受的影响很小，但阻断易化的加工状态。相反，α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）拮抗剂减少急性伤害性反应。吗啡（一种μ阿片激动剂）也可以减少急性伤害性反应。作者推测吗啡和AMPA受体拮抗剂之间的相互作用是协同的，而吗啡和NMDA拮抗剂在急性伤害性感受中没有显示出这种相互作用。Sprague-Dawley大鼠（体重，250-300 g）植入慢性腰椎鞘内导管，并被分配接受几种剂量的吗啡-ACEA 1021之一（NMDA.甘氨酸位点拮抗剂）、ACEA 2085（AMPA拮抗剂）、AP-5（NMDA拮抗剂）、盐水或赋形剂，并使用52.5 ℃热板测试它们对反应潜伏期的影响。结果：鞘内注射吗啡（ED_（50）：2 μ g/95%可信区间，1-4 μ g）和ACEA 2085（6 ng/2-15 ng），而非AP-5或ACEA 1021，可使热逃逸潜伏期呈剂量依赖性增加。使用ED 50剂量比357：1，在鞘内吗啡和ACEA 2085之间进行系统的等效线分析。观察到有效的协同作用，副作用减少。对吗啡和固定剂量的ACEA 1021（12 μ g）或AP-5（10 μ g）进行了吗啡剂量-反应曲线，没有发现协同相互作用。结论：脊髓μ受体激活和AMPA受体拮抗作用显示了对急性热刺激的协同抗伤害作用。NMDA或NMDA甘氨酸位点拮抗作用没有单独的效果，也没有显示与吗啡的协同作用。这些结果表明，急性疼痛策略的发展的一个重要方向可能集中在AMPA受体。
Background: N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a mu-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists mould be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception.Methods: Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphin-ACEA 1021 (NMDA.glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle-and were tested for their effect on the response latency using a 52.5 degrees C hot plate. The combinations of morphine and other agents also were tested.Results: Intrathecal morphine (ED50:2 mu g/95% confidence interval, 1-4 mu g) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose- response curves were carried out for morphine and fixed doses of ACEA 1021 (12 mu g) or AP-5 (10 mu g) No synergistic interactions were notedConclusions: Spinal mu-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.