Rationale

Agonists of the kappa opioid receptor (KOR) have been shown to block the rewarding effects of drugs of abuse, but with negative side effects. The antipruritic drug nalfurafine, approved in Japan in 2009, is a potent, selective KOR agonist that does not cause significant side effects in humans. Nalfurafine has not been extensively tested for its effect on drug reward and reinforcement in preclinical models.

Objectives

The goal of this study was to compare the effects of nalfurafine and a reference KOR agonist for a variety of KOR-mediated endpoints in male C57BL6 mice. Specifically, we aimed to evaluate the “therapeutic window”—doses of agonists lower than those eliciting negative side effects, while still effective for desired therapeutic effects.

Methods

In this study, several low doses of nalfurafine and U50,488 were tested for serum prolactin release, rotarod-mediated sedation, and place-conditioning in male C57BL6 mice. These agonists were also tested for effects on intravenous cocaine self-administration, both on an FR1 schedule and on a progressive ratio schedule for 0.5 mg/kg/infusion cocaine.

Results

Serum prolactin levels increased following doses of both nalfurafine (3 μg/kg and 10 μg/kg) and U50,488 (3 mg/kg). These doses did not cause sedation in the rotarod assay or aversion in a place-conditioning assay, but blocked conditioned place preference for cocaine. Immediate pretreatment of mice with 10 μg/kg nalfurafine and 3 mg/kg U50,488, however, potentiated cocaine self-administration. Further 10 μg/kg nalfurafine was also observed to potentiate cocaine-seeking behavior as demonstrated by increased progressive ratio break point.

Conclusions

Both nalfurafine and U50,488 showed a separation of negative side effects and the modulation of cocaine reward, suggesting this effect of KOR agonists at low doses may be characteristic of the KOR system in general. At higher doses, nalfurafine had similar effects to traditional KOR agonists like U50,488, indicating that its relative potency, rather than differences in KOR signaling, may be responsible for its unique effects in humans.

中文翻译：

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低剂量可卡因相关行为在雄性C57BL6小鼠中的低剂量强效KOR激动剂那拉呋芬的调节。

基本原理

Kappa阿片受体（KOR）的激动剂已被证明可以阻止滥​​用药物的奖励作用，但具有副作用。2009年在日本批准的止痒药纳氟拉芬是一种有效的选择性KOR激动剂，不会对人类造成明显的副作用。在临床前模型中，Nalfurafine对药物奖励和强化的作用尚未经过广泛测试。

目标

这项研究的目的是比较纳氟拉芬和参考KOR激动剂对雄性C57BL6小鼠各种KOR介导的终点的影响。具体来说，我们旨在评估“治疗窗口”，即激动剂的剂量低于引起负面副作用的激动剂，同时仍对所需的治疗效果有效。

方法

在这项研究中，对雄性C57BL6小鼠的血清催乳激素释放，罗塔罗德介导的镇静作用和放置条件进行了测试，使用了几种低剂量的那氟拉芬和U50,488。还测试了这些激动剂对静脉可卡因自我给药的影响，无论是在FR1方案还是在0.5 mg / kg /可卡因输液的渐进比例方案中。

结果

纳氟拉芬（3μg/ kg和10μg/ kg）和U50,488（3 mg / kg）的剂量同时导致血清催乳素水平升高。这些剂量不会在轮状仪测定中引起镇静作用，也不会在场所条件测定中引起厌恶，但是会阻止条件位置对可卡因的偏爱。立即用10μg/ kg的那氟拉芬和3 mg / kg的U50,488进行预处理，可卡因的自我给药作用增强。还观察到进一步的10μg/ kg纳氟拉芬可增强可卡因的寻找行为，如渐进比率断裂点增加所证明。

结论

纳氟拉芬和U50,488均显示出了不良副作用的分离和可卡因奖励的调节，这表明低剂量KOR激动剂的这种作用通常可能是KOR系统的特征。在较高剂量下，那拉呋芬与传统的KOR激动剂（如U50,488）具有相似的作用，这表明其相对效力而非KOR信号传导的差异可能是其对人的独特作用的原因。