Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration.
Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration.
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Cebranopadol减少了雄性大鼠的可卡因自我给药：剂量，治疗和安全考虑。
DOI：
10.1016/j.neuropharm.2020.108128
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发表时间：
2020-08-01
影响因子：
4.7
通讯作者：
Zheng, Fang
中科院分区：
文献类型：
--
作者：
Wei, Huimei;Zhang, Ting;Zhan, Chang-Guo;Zheng, Fang
作为一种新型的一流强效镇痛药，作为多种阿片受体激动剂，头孢拉多在与疼痛相关的广泛临床前模型和临床试验中表现出高效能和良好的耐受性。在本研究中，为了评估头孢拉多作为可卡因依赖的潜在治疗方法的有效性和安全性，我们使用可卡因固定比例（FR）自我给药（SA）、可卡因渐进比例（PR）SA和蔗糖颗粒SA大鼠模型测试了单次和重复剂量（25、50、75或100μg/kg，口服灌胃）头孢拉多的效果。在单剂量治疗范例中，头孢拉多在 FR 和 PR 方案下显着且剂量依赖性地减少可卡因 SA，并在 FR 方案下抑制食物摄入，而不会引起明显的副作用。在重复给药治疗方案中，即每天服用 25、50、75 或 100 μg/kg 头孢洛帕多，持续一周，可卡因摄入量也有类似的减少，而重复高剂量（75 和 100 μg/kg）时观察到不可忽视的并发症/副作用。观察到的副作用与高剂量海洛因引起的常见毒性症状相似，尽管在我们的药物辨别测试中，头孢拉多并没有完全替代海洛因的辨别性兴奋作用。这些结果表明，平衡疗效和安全性的头孢拉多最合适的口服剂量是50 μg/kg。总的来说，虽然头孢拉多可以作为可卡因依赖的新疗法，但为了提高其实际临床效用，需要更多考虑、谨慎和明确的最佳剂量窗口，以将其治疗效果与阿片类药物副作用/并发症在男性和女性受试者中区分开来。
As a novel first-in-class potent analgesic acting as an agonist of multiple opioid receptors, cebranopadol showed high efficacy and good tolerability in a broad range of preclinical models and clinical trials related to pain. In the present study, to evaluate the efficacy and safety of cebranopadol as a potential treatment of cocaine dependence, we tested the effects of cebranopadol with single and repeated doses (25, 50, 75, or 100 μg/kg, oral gavage) using rat models of cocaine fixed-ratio (FR) self-administration (SA), cocaine progressive-ratio (PR) SA, and sucrose pellet SA. In single-dosing treatment paradigm, cebranopadol significantly and dose-dependently reduced cocaine SA under FR and PR schedules and suppressed food intake under FR schedule without causing apparent side effects. In repeated-dosing treatment scheme, i.e. daily administration of 25, 50, 75, or 100 μg/kg cebranopadol for a week, the similar reduction in cocaine intake was detected, while non-negligible complications/side effects were observed at repeated high doses (75 and 100 μg/kg). The observed side effects were similar to the common toxic signs elicited by heroin at high doses, although cebranopadol did not fully substitute heroin’s discriminative stimulant effects in our drug discriminative tests. These results demonstrated that the most appropriate oral dose of cebranopadol to balance the efficacy and safety is 50 μg/kg. Collectively, although cebranopadol may serve as a new treatment for cocaine dependence, more consideration, cautiousness, and a clear optimal dose window to dissociate its therapeutic effects from opioid side effects/complications in male and female subjects will be necessary to increase its practical clinical utility.
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影响因子：
3.5
作者：
BUNZOW, JR;SAEZ, C;GRANDY, DK
通讯作者：
GRANDY, DK
影响因子：
3.4
作者：
Ciccocioppo, R;Economidou, D;Massi, M
通讯作者：
Massi, M
影响因子：
3.5
作者：
FUKUDA, K;KATO, S;SUGIMOTO, T
通讯作者：
SUGIMOTO, T
影响因子：
2.9
作者：
BUCCAFUSCO, JJ
通讯作者：
BUCCAFUSCO, JJ
影响因子：
7.6
作者：
Collins, Gregory T.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.