Baker Alexis K, Hoffmann Vincent L H, Meert Theo F
CNS Discovery Research, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium.
Pharmacol Biochem Behav. 2002 Dec;74(1):73-86. doi: 10.1016/s0091-3057(02)00961-9.
Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.
动物和临床研究报告称，氯胺酮和右美沙芬等N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可增强阿片类药物的镇痛作用。本研究的目的是比较这些临床可用的NMDA拮抗剂与经典吗啡、μ-选择性芬太尼样阿片类药物、δ-阿片受体激动剂SNC80和κ-阿片受体激动剂U50,488H联合使用的效果。采用小鼠热板试验，首先分别测定所有化合物的剂量-反应关系，然后测定与固定剂量氯胺酮或右美沙芬联合使用的阿片类药物的剂量-反应关系。所有化合物均腹腔注射给药，根据在30秒固定截止标准内未表现出任何反应的动物比例计算半数有效剂量（ED50）值。所有化合物在不同程度上均随时间延长使反应潜伏期增加。右美沙芬降低了吗啡、芬太尼和舒芬太尼的ED50值，但对SNC80或U50,488H的效力无影响。同样，氯胺酮增强了吗啡、芬太尼和舒芬太尼的镇痛效力，但对SNC80或U50,488H无影响。总之，这些结果支持μ-阿片受体激动剂与NMDA拮抗剂联合使用，但表明在急性疼痛管理中，将右美沙芬或氯胺酮与δ-或κ-阿片类药物联合使用可能没有优势。
