Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice
Improgan, a cimetidine analog, induces morphine-like antinociception in opioid receptor-knockout mice
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DOI：
10.1016/s0006-8993(00)02776-1
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发表时间：
2000-10-13
期刊：
影响因子：
2.9
通讯作者：
Pintar, JE
中科院分区：
文献类型：
--
作者：
Hough, LB;Nalwalk, JW;Pintar, JE
依美仑是H-2拮抗剂西咪替丁的类似物，其不作用于已知的组胺受体，但在啮齿动物中脑室内（icv）给药后诱导高效镇痛。由于该化合物的作用机制尚不清楚，目前在缺乏mu. (exon 1）、δ（DOR-1的外显子2）或κ（KOR-1的外显子3）阿片受体。依莫司坦（30 μ g，冰冷）在给药后10和20分钟，在所有三种基因型（+/+，+/-和-/-）的莫尔-1突变小鼠的两种性别中诱导可逆的最大镇痛作用，而在这些受试者中吗啡镇痛作用减少（+/-）或消除（-/-）。在DOR-1突变小鼠中，尽管δ阿片受体（H-3-[D-Pen（2），D-Pen（5）]脑啡肽）减少（+/-）或完全丧失（-/-），但Improgan在所有三种基因型中同样有效。DPDPE）结合。类似地，在所有三种基因型的KOR-1突变小鼠中，不适当的镇痛是等效的，而在纯合（-/-）小鼠中，κ介导的镇痛（U 50，488）和κ阿片样物质（H-3-U69，593）结合被消除。这些研究表明，不适当的镇痛不需要完整的MOR-1，DOR-1。或KOR-I基因，并支持promogan样镇痛药通过非阿片类机制在中枢神经系统中发挥作用的假设。(C)2000 Elsevier Science B. V.保留所有权利。
Improgan is an analog of the H-2 antagonist cimetidine that does not act on known histamine receptors, but induces highly effective analgesia in rodents following intracerebroventricular (icv) administration. Since the mechanism of action of this compound remains unknown, improgan analgesia was characterized presently with the tail immersion nociceptive test in mutant mice lacking either the mu. (exon 1 of MOR-1), delta (exon 2 of DOR-1) or kappa (exon 3 of KOR-1) opioid receptor. Improgan (30 mug, icy) induced reversible, maximal analgesia in both sexes of all three genotypes (+/+, +/- and -/-) of MOR-1 mutant mice 10 and 20 min after administration, whereas morphine analgesia was reduced (+/-) or abolished (-/-) in these subjects. In DOR-1 mutant mice, improgan was equally effective in all three genotypes, despite the reduction (+/-) or complete loss (-/-) of delta opioid receptor (H-3-[D-Pen(2),D-Pen(5)]enkephalin. DPDPE) binding. Similarly, improgan analgesia was equivalent in all three genotypes of KOR-1 mutant mice, whereas kappa -mediated analgesia (U50,488) and kappa opioid (H-3-U69,593) binding were abolished in the homozygous (-/-) mice. These studies demonstrate that improgan analgesia does not require intact MOR-I, DOR-1. or KOR-I genes, and support the hypothesis that improgan-like analgesics act in the CNS by non-opioid mechanisms. (C) 2000 Elsevier Science B.V. All rights reserved.