在海洛因维持的大鼠中通过固定和累进比率静脉自我给药测试研究萨米多福和纳曲酮的增强潜力。

Investigation of the reinforcing potential of samidorphan and naltrexone by fixed and progressive ratio intravenous self-administration testing in heroin-maintained rats.

机构信息

1 RenaSci Ltd, BioCity, Nottingham, UK.

2 Alkermes, Inc., Waltham, MA, USA.

出版信息

J Psychopharmacol. 2019 Mar;33(3):383-391. doi: 10.1177/0269881118822111. Epub 2019 Jan 24.

DOI:10.1177/0269881118822111

PMID:30676189

Abstract

BACKGROUND

Samidorphan is a novel μ-opioid antagonist with low intrinsic activity at κ- and δ-opioid receptors.

AIMS

Because samidorphan is central nervous system-active, we investigated whether samidorphan (13.6, 40.8, 68 μg/kg/injection) served as a positive reinforcer in rats trained to self-administer heroin on a fixed ratio-5 schedule. Samidorphan's relative reinforcing effect was evaluated by progressive ratio/break-point determination. Naltrexone (13.6, 40.8, 68 μg/kg/injection) and heroin (7.5, 15, 25 μg/kg/injection) were comparators.

RESULTS

All heroin doses maintained self-administration on fixed ratio-5 and progressive ratio/break-points at levels significantly greater than saline. Samidorphan and naltrexone had similar profiles on fixed ratio-5 with one samidorphan dose serving as a positive reinforcer and one naltrexone dose showing a strong trend ( p=0.053) for positive reinforcement. The numbers of injections of every samidorphan and naltrexone dose were significantly lower than all heroin doses. The numbers of self-administered samidorphan and naltrexone injections/session on fixed ratio-5 were not significantly different from one another. The mean inter-injection intervals for heroin were significantly shorter than for saline, whereas those of samidorphan and naltrexone were not. Progressive ratio break-points for samidorphan and naltrexone were not different from saline except for the highest dose of samidorphan. In addition, the progressive ratio break-points for samidorphan were not significantly different from those of naltrexone and were significantly lower than heroin. The samidorphan unit-doses evaluated in self-administration yielded plasma concentrations ranging between 25-109% and 10-45% of the maximum concentration values in humans.

CONCLUSIONS

Overall, the profiles of samidorphan and naltrexone, which has no abuse liability, were similar in this model.

摘要

背景

萨米多弗是一种新型μ阿片受体拮抗剂，对κ和δ阿片受体的内在活性较低。

目的

由于萨米多弗具有中枢神经系统活性，我们研究了萨米多弗（13.6、40.8、68μg/kg/注射）是否在经过训练以固定比率 5 自我注射海洛因的大鼠中作为正强化物。通过递增比例/断点测定来评估萨米多弗的相对强化作用。纳曲酮（13.6、40.8、68μg/kg/注射）和海洛因（7.5、15、25μg/kg/注射）为比较剂。

结果

所有海洛因剂量均维持固定比率 5 和递增比例/断点的自我给药水平，显著高于盐水。萨米多弗和纳曲酮在固定比率 5 上具有相似的特征，一种萨米多弗剂量作为正强化物，一种纳曲酮剂量显示出正强化的强烈趋势（p=0.053）。每个萨米多弗和纳曲酮剂量的注射次数均明显低于所有海洛因剂量。萨米多弗和纳曲酮的固定比率 5 自我给药注射次数彼此之间没有显著差异。海洛因的平均注射间隔明显短于盐水，而萨米多弗和纳曲酮的注射间隔则不然。除了萨米多弗的最高剂量外，萨米多弗和纳曲酮的递增比例断点与盐水没有差异。此外，萨米多弗的递增比例断点与纳曲酮没有显著差异，明显低于海洛因。在自我给药中评估的萨米多弗单位剂量产生的血浆浓度范围在 25-109%和 10-45%之间，处于人类的最大浓度值。