Shippenberg T S, Heidbreder C, Lefevour A
Preclinical Pharmacology Laboratory, NIH/NIDA Division of Intramural Research, Baltimore, MD 21224, USA.
Eur J Pharmacol. 1996 Mar 28;299(1-3):33-9. doi: 10.1016/0014-2999(95)00852-7.
An unbiased place preference conditioning procedure was used to determine whether the repeated administration of morphine results in sensitization to its conditioned rewarding effects. Rats received once daily injections of saline or morphine (5.0 mg/kg; i.p.) for 5 days in a room distinct from that where conditioning would occur. Place preference conditioning commenced 72 h later. A minimum of three drug conditioning sessions was necessary for the establishment of morphine-induced conditioned place preferences in saline-pretreated rats. The minimum dose producing this effect was 5.0 mg/kg. In animals pre-exposed to morphine, significant place preferences occurred after only two drug conditioning sessions and in response to doses of 3.0 mg/kg and greater. The augmented response to morphine was apparent when conditioning commenced 3, 10 or 21 days after the cessation of morphine pretreatment. It was not apparent when conditioning commenced 1 day after treatment cessation. An enhanced response to morphine was also observed in rats which had previously received either fentanyl (0.016 mg/kg/day) or nicotine (0.4 mg/kg/day) for 5 days. Animals which received morphine or fentanyl in combination with naloxone (0.5 mg/kg; s.c.) for 5 days failed to exhibit a conditioned response to morphine. When, however, naloxone was administered in combination with nicotine, significant morphine-induced place preferences were still seen. These data demonstrate that both sensitization and cross-sensitization develop to the conditioned rewarding effects of morphine. Furthermore, they indicate that the sensitization induced by morphine and fentanyl, but not nicotine, is opioid-receptor mediated.
采用无偏倚的位置偏爱条件反射程序来确定吗啡的重复给药是否会导致对其条件性奖赏效应的敏感化。大鼠在与条件反射发生房间不同的房间内，每天接受一次生理盐水或吗啡（5.0毫克/千克；腹腔注射）注射，持续5天。72小时后开始位置偏爱条件反射。对于用生理盐水预处理的大鼠，要建立吗啡诱导的条件性位置偏爱，最少需要三次药物条件反射实验。产生这种效应的最小剂量是5.0毫克/千克。在预先接触过吗啡的动物中，仅在两次药物条件反射实验后，且对3.0毫克/千克及以上剂量就出现了明显的位置偏爱。当在吗啡预处理停止后3天、10天或21天开始条件反射时，对吗啡的增强反应很明显。在治疗停止后1天开始条件反射时则不明显。在先前接受过5天芬太尼（0.016毫克/千克/天）或尼古丁（0.4毫克/千克/天）的大鼠中，也观察到对吗啡的反应增强。接受吗啡或芬太尼与纳洛酮（0.5毫克/千克；皮下注射）联合注射5天的动物，对吗啡未表现出条件性反应。然而，当纳洛酮与尼古丁联合给药时，仍能看到明显的吗啡诱导的位置偏爱。这些数据表明，对吗啡的条件性奖赏效应会产生敏感化和交叉敏感化。此外，它们表明吗啡和芬太尼诱导的敏感化是由阿片受体介导的，而尼古丁诱导的不是。
