Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice.
Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice.
复制标题
口服生物利用的短作用Kappa阿片受体选择性拮抗剂LY2456302对小鼠尼古丁戒断的影响。
DOI：
10.1016/j.neuropharm.2015.05.023
复制
发表时间：
2015-10
影响因子：
4.7
通讯作者：
Damaj MI
中科院分区：
文献类型：
--
作者：
Jackson KJ;Jackson A;Carroll FI;Damaj MI
κ阿片受体（KOR）信号转导参与介导与药物依赖相关的行为和生化效应。最常用的KOR拮抗剂norbinaltorphimine（norBNI）和（3R）-7-羟基-N {（1 S）-1-{[（3R，4 R）-4-（3-羟基苯基）-3，4-二甲基-1-哌啶基]甲基}-2-甲基丙基}-1，2，3，4-四氢-3-异喹啉-甲酰胺（JDTic）在这一领域提供了丰富的信息;然而，这些拮抗剂的延迟起效和持久作用使实验设计和结果解释复杂化，并使它们对于临床研究不太理想。最近开发的KOR拮抗剂LY 2456302的初步研究表明，该化合物是一种短效、高亲和力、选择性的KOR拮抗剂，在动物模型中对情绪障碍和乙醇使用具有治疗潜力，并且在人体中耐受良好。本研究的目的是评价LY 2456302在缓解小鼠尼古丁戒断综合征方面的有效性。小鼠接受尼古丁长期治疗14天，并在口服LY 2456302预治疗后，使用自发尼古丁戒断模型和条件性位置厌恶（CPA）测量身体和情感尼古丁戒断体征。溶剂处理的尼古丁戒断小鼠显示出显著的焦虑相关行为、躯体体征、痛觉过敏和CPA。与先前使用norBNI和JDTic的研究类似，LY 2456302减轻尼古丁戒断综合征，如通过尼古丁戒断诱导的焦虑相关行为、躯体体征和CPA的表达降低以及预处理后尼古丁戒断小鼠中热板潜伏期增加所证明的。鉴于目前的结果，以及其良好的药代动力学和药效学特征，LY 2456302可能是一种有用的治疗药物，用于治疗尼古丁戒断综合征的多个方面。
Kappa opioid receptor (KOR) signaling has been implicated in mediating behavioral and biochemical effects associated with drug dependence. The most commonly used KOR antagonists, norbinaltorphimine (norBNI) and (3R)-7-Hydroxy-N{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), have provided a wealth of information in this area; however, the delayed onset and long-lasting effects of these antagonists complicate experimental design and interpretation of results, and make them less than ideal for clinical studies. Initial studies with the recently developed KOR antagonist, LY2456302, show that the compound is a short acting, high-affinity, selective KOR antagonist with therapeutic potential for mood disorders and ethanol use in animal models, and is well tolerated in humans. The goal of the current study was to evaluate the effectiveness of LY2456302 in alleviating the nicotine withdrawal syndrome in mice. Mice were chronically treated with nicotine for 14 days and physical and affective nicotine withdrawal signs were measured using a spontaneous nicotine withdrawal model and conditioned place aversion (CPA) following pre-treatment with LY2456302, administered orally. Vehicle treated nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs, hyperalgesia, and CPA. Similar to previous studies with norBNI and JDTic, LY2456302 alleviated the nicotine withdrawal syndrome, as evidenced by decreased expression of nicotine withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment. Given the current results, and with its favorable pharmacokinetic and pharmacodynamic profile, LY2456302 may be a useful therapeutic agent for treatment of multiple aspects of the nicotine withdrawal syndrome.