Rasmussen K, Fuller R W, Stockton M E, Perry K W, Swinford R M, Ornstein P L
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Eur J Pharmacol. 1991 May 2;197(1):9-16. doi: 10.1016/0014-2999(91)90358-w.
Pretreatment with the non-competitive NMDA (N-methyl-D-aspartate) antagonist MK801 (0.5, 1.0 mg/kg, s.c.) suppressed the behavioral signs of withdrawal in morphine-dependent rats. However, the same doses of MK801 that suppressed morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behaviors. Pretreatment with the competitive NMDA antagonist LY274614 (25, 50, 100 mg/kg i.p.) also suppressed the behavioral signs of withdrawal in morphine-dependent rats but did not produce PCP-like behavioral effects. Single unit recordings were made from noradrenergic neurons in the locus coeruleus (LC) and, at doses that suppressed morphine withdrawal behaviors, neither MK801 nor LY274614 blocked the withdrawal-induced activation of LC neurons. Biochemical analysis indicated that, at the same behaviorally relevant doses, neither MK801 nor LY274614 blocked the withdrawal-induced increase in norepinephrine turnover in the hippocampus, cerebral cortex, or hypothalamus. These results indicate that NMDA antagonists attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase in norepinephrine turnover or the withdrawal-induced increase in LC unit activity. In addition, non-competitive NMDA antagonists, like MK801, may not be useful to alleviate opiate withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists, like LY274614, could be of great benefit for alleviating opiate withdrawal symptoms in man.
用非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂MK801（0.5、1.0毫克/千克，皮下注射）对吗啡依赖大鼠进行预处理，可抑制其戒断行为体征。然而，同样能抑制吗啡戒断的MK801剂量同时也会产生苯环己哌啶（PCP）样行为。用竞争性NMDA拮抗剂LY274614（25、50、100毫克/千克，腹腔注射）进行预处理，也可抑制吗啡依赖大鼠的戒断行为体征，但不会产生PCP样行为效应。对蓝斑（LC）中的去甲肾上腺素能神经元进行单单位记录，在能抑制吗啡戒断行为的剂量下，MK801和LY274614均未阻断戒断诱导的LC神经元激活。生化分析表明，在行为相关的相同剂量下，MK801和LY274614均未阻断戒断诱导的海马体、大脑皮层或下丘脑去甲肾上腺素周转率的增加。这些结果表明，NMDA拮抗剂可减轻吗啡戒断的行为体征，而不阻断戒断诱导的去甲肾上腺素周转率增加或戒断诱导的LC单位活动增加。此外，像MK801这样的非竞争性NMDA拮抗剂，由于其PCP样副作用，可能对缓解人类阿片类药物戒断症状无用。然而，像LY274614这样的竞争性NMDA拮抗剂可能对缓解人类阿片类药物戒断症状有很大益处。
