Brandt M R, France C P
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans, Louisiana, USA.
J Pharmacol Exp Ther. 1998 Dec;287(3):1029-37.
This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.
本研究对纳曲酮在每日接受长效阿片类药物左旋-α-乙酰美沙多（LAAM）治疗的恒河猴中的辨别性刺激及其他效应进行了特征描述。一项初始剂量探索研究评估了纳曲酮对三只每日接受LAAM（0.32 - 1.78毫克/千克）的猴子的速率降低效应；随后，这三只猴子和第四只猴子接受了1.0毫克/千克/12小时的LAAM，同时区分纳曲酮和生理盐水。给予LAAM后，在生理盐水杠杆上出现反应，而给予0.1毫克/千克纳曲酮后，超过90%的药物杠杆反应出现，同时还引发了戒断症状。纳洛酮和夸达佐辛可替代纳曲酮，但吗啡、纳布啡或氯胺酮则不能。吗啡和纳布啡使纳曲酮剂量效应曲线右移。与戒断引发的戒断相比，剥夺诱导的戒断引发的纳曲酮杠杆反应较少，可观察到的戒断症状也较少。纳曲酮水平的最大反应出现在LAAM治疗停药后24至48小时；其他戒断症状的频率在LAAM停药后24至48小时也达到峰值。LAAM治疗停药后，纳曲酮杠杆反应持续长达10天；LAAM治疗停药后4天和8天，0.1毫克/千克的纳曲酮不再进一步增加纳曲酮杠杆反应或戒断症状，这表明低于最大程度的纳曲酮杠杆反应并非由于LAAM或其代谢产物的长期效应。与LAAM剥夺相关的辨别性刺激可能与任何一种训练条件相关的刺激不同。本研究是首次在长期接受LAAM治疗的非人类灵长类动物中进行拮抗剂辨别，结果表明纳曲酮刺激与阿片类药物戒断有关。
