Schulteis G, Heyser C J, Koob G F
Department of Anesthesiology, UC San Diego School of Medicine 92161-5085, USA.
Behav Pharmacol. 1999 May;10(3):235-42. doi: 10.1097/00008877-199905000-00001.
The current study examined the conditions that are necessary and sufficient for the initiation and progression of acute morphine dependence using two indices of opiate withdrawal: suppression of operant response rates and a somatic withdrawal rating scale. Separate groups of rats were pretreated with morphine (5 mg/kg, s.c.) a total of three times at intervals of 24 h, 1, 3, or 6 weeks. Rats received a single dose of naloxone 4 h after each morphine pretreatment. Naloxone-induced suppression of operant responding (0.33 mg/kg, s.c.) was significantly potentiated with repeated exposure to morphine even at the 6-week inter-treatment interval (ITI). At 24-h, 1-week and 3-week ITIs, rats treated with naloxone only after the third and final morphine pretreatment showed similar suppression of operant responding following naloxone to rats treated with naloxone after all three morphine pretreatments. However, at the 6-week ITI, the response-disruptive effects of naloxone administered for the first time after the third morphine pretreatment were no greater than the effects of naloxone administered after a single morphine pretreatment. In contrast to results seen with suppression of operant responding as the withdrawal index, potentiation of somatic signs of withdrawal was observed only at the 24-h ITI. These results indicate that a neuroadaptive state resembling opiate dependence can be initiated after just one injection of morphine, and that the response-disruptive effects of naloxone appear to be a particularly sensitive index of the initiation and progression of acute opiate dependence.
操作性反应率的抑制和躯体戒断评定量表，来检测急性吗啡依赖起始和进展所必需且充分的条件。将大鼠分为不同组，分别用吗啡（5毫克/千克，皮下注射）预处理，共三次，间隔时间为24小时、1周、3周或6周。每次吗啡预处理后4小时，大鼠接受单剂量纳洛酮。即使在6周的治疗间隔期（ITI），反复接触吗啡后，纳洛酮诱导的操作性反应抑制（0.33毫克/千克，皮下注射）也显著增强。在24小时、1周和3周的ITI时，仅在第三次也是最后一次吗啡预处理后用纳洛酮处理的大鼠，与在所有三次吗啡预处理后用纳洛酮处理的大鼠相比，纳洛酮处理后操作性反应的抑制情况相似。然而，在6周的ITI时，第三次吗啡预处理后首次给予纳洛酮的反应干扰效应不大于单次吗啡预处理后给予纳洛酮的效应。与以操作性反应抑制作为戒断指标所观察到的结果相反，仅在24小时的ITI时观察到躯体戒断体征的增强。这些结果表明，仅一次注射吗啡后就能引发类似阿片类药物依赖的神经适应性状态，并且纳洛酮的反应干扰效应似乎是急性阿片类药物依赖起始和进展的一个特别敏感的指标。
