Funada M, Schutz C G, Shippenberg T S
Clinical Pharmacology Branch, National Institute on Drug Abuse, National Institute of Health, Baltimore, MD 21224, USA.
Eur J Pharmacol. 1996 Apr 4;300(1-2):17-24. doi: 10.1016/0014-2999(95)00860-8.
An unbiased place preference conditioning procedure was used to examine the role of delta-opioid receptors in mediating the aversive effects of opioid withdrawal. Rats were implanted s.c. with two pellets each containing placebo or 75 mg morphine. Single-trial conditioning sessions with saline and the opioid receptor antagonists naloxone (0.001-1.0 mg/kg, s.c.), naltrindole (0.01-3.0 mg/kg, s.c.) or naltriben (0.01-3.0 mg/kg, s.c.) commenced 4 days later. During these conditioning sessions, physical signs of withdrawal were also quantified. Tests of conditioning were conducted on day 5. Naloxone in doses of 0.01-1.0 mg/kg produced significant conditioned place aversions in morphine-implanted animals. A dose of 0.01 mg/kg produced few physical withdrawal signs whereas higher doses resulted in marked wet dog shakes, body weight loss ptosis and diarrhea. No such effects were observed in control (placebo-implanted) animals. Administration of the selective delta-opioid receptor antagonists naltrindole and naltriben produced dose-related place aversions in morphine-implanted animals. The magnitude of these effects did not differ from that observed with naloxone. The minimum effective doses of naltrindole and naltriben were 0.1 mg/kg. Doses of 0.1-1.0 mg/kg produced few, if any, somatic signs of withdrawal whereas higher doses of these antagonists only produced diarrhea and wet-dog shakes. Other withdrawal signs were absent. In contrast to the opioid receptor antagonists tested, the dopamine D1 receptor antagonist SCH23390 failed to produced conditioned place aversions or physical signs of withdrawal in morphine-pelleted animals. These data demonstrate that the selective blockade of either delta- or mu-opioid receptors is sufficient to induce conditioned aversive effects in morphine-dependent animals. They also indicate that physical symptoms associated with precipitated morphine withdrawal differ depending upon the opioid receptor antagonist employed.
采用无偏性位置偏爱条件反射程序来研究δ-阿片受体在介导阿片类药物戒断厌恶效应中的作用。给大鼠皮下植入两个含有安慰剂或75毫克吗啡的药丸。4天后开始用生理盐水以及阿片受体拮抗剂纳洛酮（0.001 - 1.0毫克/千克，皮下注射）、纳曲吲哚（0.01 - 3.0毫克/千克，皮下注射）或纳曲苄（0.01 - 3.0毫克/千克，皮下注射）进行单次条件反射实验。在这些条件反射实验期间，还对戒断的身体体征进行了量化。在第5天进行条件反射测试。0.01 - 1.0毫克/千克剂量的纳洛酮在植入吗啡的动物中产生了显著的条件性位置厌恶。0.01毫克/千克的剂量产生的身体戒断体征很少，而较高剂量则导致明显的湿狗样抖动、体重减轻、眼睑下垂和腹泻。在对照（植入安慰剂）动物中未观察到此类效应。给予选择性δ-阿片受体拮抗剂纳曲吲哚和纳曲苄在植入吗啡的动物中产生了剂量相关的位置厌恶。这些效应的程度与用纳洛酮观察到的没有差异。纳曲吲哚和纳曲苄的最小有效剂量为0.1毫克/千克。0.1 - 1.0毫克/千克的剂量产生的躯体戒断体征很少（如果有的话），而这些拮抗剂的较高剂量仅产生腹泻和湿狗样抖动。没有其他戒断体征。与所测试的阿片受体拮抗剂不同，多巴胺D1受体拮抗剂SCH23390在植入吗啡药丸的动物中未能产生条件性位置厌恶或戒断的身体体征。这些数据表明，选择性阻断δ-或μ-阿片受体足以在吗啡依赖的动物中诱导条件性厌恶效应。它们还表明，与突然停用吗啡相关的身体症状因所用的阿片受体拮抗剂而异。
