Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine

作     者：Fairbanks, CA Wilcox, GL 

作者机构：Univ Minnesota Dept Pharmacol Minneapolis MN 55455 USA Univ Minnesota Grad Program Neurosci Minneapolis MN 55455 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第288卷第3期

页      面：1107-1116页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：NIDA NIH HHS [R01-DA-04274, R01-DA-01933] Funding Source: Medline PHS HHS [T32A07234] Funding Source: Medline 

主　　题：镇痛药/药理学 镇痛药 阿片类/药理学 可乐定/药理学 剂量效应关系 药物 复方合剂 药物协同作用 药物耐受性 注射 脊髓 注射 皮下 小鼠 近交ICR 吗啡/投药和剂量 吗啡/药理学 尾 时间因素 动物 男(雄)性 小鼠 

摘      要：Morphine (Mor) tolerance has been attributed to a reduction of opioid-adrenergic antinociceptive synergy at the spinal level. The present experiments tested the interaction of intrathecally (i.t.) administered Mor-clonidine (Clon) combinations in mice made acutely or chronically tolerant to Mor. ICR mice were pretreated with Mor either acutely (40 nmol i.t., 8 h;100 mg/kg s.c., 4 h) or chronically (3 mg/kg s.c. every 6 h days 1 and 2;5 mg/kg s.c. every 6 h days 3 and 4). Antinociception was detected via the hot water (52.5 degrees C) tail-flick test. After the tail-flick latencies returned to baseline levels, dose-response curves were generated to Mor, Cion, and Mor-Clon combinations in tolerant and control mice. Development of tolerance was confirmed by significant rightward shifts of the Mor dose-response curves in tolerant mice compared with controls. Isobolographic analysis was conducted;the experimental combined ED50 values were compared statistically against their respective theoretical additive ED50 values. In all Mor-pretreated groups, the combination of Mor and Cion resulted in significant leftward shifts in the dose response curves compared with those of each agonist administered separately. In all tolerant and control groups, the combination of Mor and Cion produced an ED50 value significantly less than the corresponding theoretical additive ED50 value. Mor and Cion synergized in Mor-tolerant as well as in control mice. Spinally administered adrenergic/opioid synergistic combinations may be effective therapeutic strategies to manage pain in patients apparently tolerant to the analgesic effects of Mor.