Stevens C W, Yaksh T L
Department of Pharmacology and Laboratory of Neurosurgical Research, Mayo Clinic, Rochester, MN 55905.
Eur J Pharmacol. 1989 Aug 3;166(3):467-72. doi: 10.1016/0014-2999(89)90360-9.
The continuous intrathecal infusion of morphine (2, 6, 20 nmol/h), sufentanil (0.06, 0.2, 0.6 nmol/h), [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAMGO) (0.1, 0.3, 1.0 nmol/h) or [D-Ala2,D-Leu5]enkephalin (DADLE) (2, 6, 20 nmol/h) in unanesthetized rats produces a dose-dependent increase in hot plate latency 1 day after pump implant followed by a gradual return to baseline values by days 3-4, i.e. tolerance. Rats assessed for opioid dependence after 7 days of intrathecal (i.t.) infusion of opioids show a withdrawal syndrome most readily noted by withdrawal body shakes (WBS) after injection of the opioid antagonist, naloxone (1 mg/kg i.p.). The number of WBS was proportional to the infusion dose of opioid agonist. Although each tolerance-producing agent was infused in one of three log-spaced (low, medium, high) doses, selected to have approximately equal antinociceptive activity across agents, the agents varied in the apparent degree of dependence. Thus, at the highest infusion dose, the average number of WBS observed was greatest for DADLE (32.8), morphine (30.2) and sufentanil (25.0) while animals treated with DAMGO displayed a significantly less degree of opioid dependence (8.7).
在未麻醉的大鼠中持续鞘内输注吗啡（2、6、20纳摩尔/小时）、舒芬太尼（0.06、0.2、0.6纳摩尔/小时）、[D-丙氨酸²，甲硫氨酸⁴，甘醇⁵]脑啡肽（DAMGO）（0.1、0.3、1.0纳摩尔/小时）或[D-丙氨酸²，D-亮氨酸⁵]脑啡肽（DADLE）（2、6、20纳摩尔/小时），在植入泵后1天会使热板潜伏期出现剂量依赖性增加，随后在第3 - 4天逐渐恢复到基线值，即产生耐受性。在鞘内（i.t.）输注阿片类药物7天后评估阿片类药物依赖性的大鼠，在注射阿片类拮抗剂纳洛酮（1毫克/千克腹腔注射）后会出现戒断综合征，最容易观察到的是戒断性身体抖动（WBS）。WBS的数量与阿片类激动剂的输注剂量成正比。尽管每种产生耐受性的药物都以三个对数间隔（低、中、高）剂量之一进行输注，选择这些剂量是为了使各药物具有大致相等的抗伤害感受活性，但这些药物在明显的依赖程度上有所不同。因此，在最高输注剂量下，观察到的DADLE（32.8）、吗啡（30.2）和舒芬太尼（25.0）的WBS平均数量最多，而用DAMGO治疗的动物表现出的阿片类药物依赖性程度明显较低（8.7）。
