Tortella F C, Moreton J E, Khazan N
J Pharmacol Exp Ther. 1979 Aug;210(2):174-9.
Rats were given repeated intraventricular (i.vt.) injections of D-enkephalin (20 microgram/4 hr) or morphine (20 microgram/4 hr) for 72 to 96 hr during electroencephalograman(EEG) recording. Initial epileptiform EEG and associated wet-dog shakes occurred following D-enkephalin but not morphine. The epileptoid EEG progressed to a continous high-voltage EEG synchrony similar to morphine and was associated with behavioral stupor. Rapid eye movement sleep was also suppressed. Repeated administration of D-enkephalin or morphine produced tolerance to their effects. When challenged with i.vt. morphine, D-enkephalin-tolerant rats were cross-tolerant to morphine. Likewise, morphine-tolerant rats were cross-tolerant to D-enkephalin. While the morphine-tolerant rats demonstrated a marked abstinence syndrome when challenged with naloxone (10 mg/kg i.p.), no abstinence signs were observed in the D-enkephalin-tolerant rats. The demonstration of tolerance and cross-tolerance between morphine and D-enkephalin suggests a similar mechanism of action, but the differential development of physical dependence may entail different mechanisms or receptor sensitivities for this effect. These findings of similarities and differences in the acute and chronic effects of D-enkephalin and morphine support the contention that heterogenous opiate receptors may mediate their pharmacologic actions.
在脑电图（EEG）记录期间，给大鼠反复脑室内（i.vt.）注射D-脑啡肽（20微克/4小时）或吗啡（20微克/4小时），持续72至96小时。注射D-脑啡肽后出现初始癫痫样EEG及相关的湿狗样抖动，而注射吗啡后则未出现。癫痫样EEG进展为类似于吗啡的持续高电压EEG同步，并伴有行为昏迷。快速眼动睡眠也受到抑制。反复给予D-脑啡肽或吗啡会产生对其作用的耐受性。当脑室内注射吗啡进行激发试验时，对D-脑啡肽耐受的大鼠对吗啡产生交叉耐受性。同样，对吗啡耐受的大鼠对D-脑啡肽也产生交叉耐受性。虽然对吗啡耐受的大鼠在注射纳洛酮（10毫克/千克腹腔注射）进行激发试验时表现出明显的戒断综合征，但在对D-脑啡肽耐受的大鼠中未观察到戒断迹象。吗啡和D-脑啡肽之间耐受性和交叉耐受性的表现表明它们有相似的作用机制，但身体依赖性的差异发展可能涉及不同的机制或受体敏感性。D-脑啡肽和吗啡在急性和慢性作用方面这些异同的发现支持了这样的观点，即不同的阿片受体可能介导它们的药理作用。
