Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed k/μ receptor antagonist properties, in mice
Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed k/μ receptor antagonist properties, in mice
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DOI：
10.1111/bph.14060
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发表时间：
2018-07-01
影响因子：
7.3
通讯作者：
Bailey, Sarah J.
中科院分区：
文献类型：
--
作者：
Almatroudi, Abdulrahman;Ostovar, Mehrnoosh;Bailey, Sarah J.
背景与目的受体拮抗剂具有治疗神经精神疾病的潜力。本文首次研究了一种新的丁丙诺啡类似物BU 10119的体内药理学。在体内，在成年雄性CD 1小鼠中应用温水尾戒断试验。使用一系列行为范例来研究BU 10119的运动效应、奖励特性和抗抑郁或抗焦虑潜力。将另外几组小鼠暴露于单次（1 × 2小时）或重复的束缚应激（3 ×每天2小时），以确定BU 10119阻断应激诱导的镇痛作用的能力。BU 10119（1 mg·kg ~（-1））能阻断U_（50）、488、丁丙诺啡和吗啡诱导的镇痛作用。BU 10119在尾部撤回试验中的拮抗作用在24和48小时之间逆转。BU 10119没有显著的运动或奖励效应。与生理盐水处理的动物相比，BU 10119（1 mg/kg）显著缩短了新奇诱导的食欲减退任务中的进食潜伏期，并缩短了强迫游泳试验中的不动时间。BU 10119在高架十字迷宫或明暗箱中均无显著作用。急性和反复束缚应激镇痛作用均被BU 10119（1 mg/kg）阻断。平行的压力引起的血浆皮质酮的增加没有受到影响。结论和ImplicationsBU 10119是一种混合/受体拮抗剂，具有相对较短的拮抗剂活性。基于这些临床前数据，BU 10119具有治疗抑郁症和其他应激诱导疾病的治疗潜力。
Background and PurposeThe receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time.Experimental ApproachTo determine the opioid pharmacology of BU10119 (0.3-3mgkg(-1), i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1x2h) or repeated restraint stress (3x daily 2h) to determine the ability of BU10119 to block stress-induced analgesia.Key ResultsBU10119 alone was without any antinociceptive activity. BU10119 (1mgkg(-1)) was able to block U50,488, buprenorphine and morphine-induced antinociception. The antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1mgkg(-1)) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light-dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1mgkg(-1)). Parallel stress-induced increases in plasma corticosterone were not affected.Conclusions and ImplicationsBU10119 is a mixed / receptor antagonist with relatively short-duration antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions.