The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration
The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration
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DOI：
10.1111/bph.12132
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发表时间：
2013-05-01
影响因子：
7.3
通讯作者：
McLaughlin, Jay P.
中科院分区：
文献类型：
--
作者：
Eans, Shainnel O.;Ganno, Michelle L.;McLaughlin, Jay P.
背景和目的环肽对蛋白水解裂解具有抗性，因此在全身给药后可能表现出活性。我们假设，大环阿片受体（KOR）选择性拮抗剂[D-Trp]CJ-15，208在全身性，即s.c.和口服（经口，p.o.），局实验方法用[D-Trp]CJ-15，208 s. c.或邮政在给予KOR选择性激动剂U 50，488之前，并在温水尾戒断试验中测定抗伤害感受。用[D-Trp]CJ-15，208处理的小鼠的运动活性通过旋转棒测试来测定。每天用媒介物或[D-Trp]CJ-15，208预处理表现出可卡因条件性位置偏好和随后消退的另外的小鼠，然后在重新确定位置偏好之前暴露于重复的强迫游泳应激或单次额外的可卡因位置条件作用。用[D-Trp]CJ-15，208皮下给药的预处理或邮政在小鼠温水缩尾实验中，剂量依赖性地拮抗U_（50），488诱导的抗伤害性感受作用，分别为少于12和6 h。2019 - 05 - 25 00：00：00 00 00：00 00
Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D-Trp]CJ-15,208s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6h respectively. [D-Trp]CJ-15,208 also produced limited (