Hiramatsu Masayuki, Mizuno Natsuko, Kanematsu Ken
Laboratory of Neuropsychopharmacology, Graduate School of Environmental and Human Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan.
Behav Brain Res. 2006 Feb 28;167(2):219-25. doi: 10.1016/j.bbr.2005.09.009. Epub 2005 Oct 11.
3-Acetoxy-6beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) is a synthesized compound that binds to mu-, delta- and kappa-opioid receptors in vitro. KT-95 induces analgesia and this effect is antagonized by nor-BNI, a selective kappa-opioid receptor antagonist. We have reported that kappa-opioid receptor agonists improve impairment of learning and memory in mice and/or rats. In this study, the effects of KT-95 were investigated in an acetic acid-induced writhing test and scopolamine-induced memory impairment test using spontaneous alternation performance in a Y-maze and a step-down type passive avoidance test. Male ddY mice were treated with KT-95 (0.24-2.35 micromol/kg, s.c.) 30 min before the behavioral test. In the writhing test, the antinociceptive effect of KT-95 (2.35 micromol/kg) was completely antagonized by nor-BNI (4.9 nmol/mouse, i.c.v.), but not by naloxone (3.05 micromol/kg, s.c.). KT-95 significantly improved the impairment of spontaneous alternation induced by scopolamine (1.65 micromol/kg, s.c.). The ameliorating effect of KT-95 was not antagonized by nor-BNI, but was almost completely antagonized by a selective sigma-receptor antagonist, N,N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride (NE-100, 2.6 micromol/kg, i.p.). KT-95 also significantly improved scopolamine-induced learning and memory impairment in the passive avoidance test, although the effect was partial. Administration of KT-95 itself induced impairment of learning and memory. KT-95-induced impairment was not antagonized by naloxone, naltrindole, nor-BNI or NE-100 indicating that this impairment was not because of opioid receptor stimulation. These results suggested that although the KT-95-induced antinociceptive effect was mediated by kappa-opioid receptors, the KT-95-induced improvement in scopolamine-induced impairment of memory was mediated mainly via sigma-receptors and partially by kappa-opioid receptors.
3-乙酰氧基-6β-乙酰硫基-10-氧代-N-环丙基甲基-二氢去甲吗啡（KT-95）是一种合成化合物，在体外可与μ-、δ-和κ-阿片受体结合。KT-95可诱导镇痛，且这种作用可被选择性κ-阿片受体拮抗剂nor-BNI拮抗。我们曾报道κ-阿片受体激动剂可改善小鼠和/或大鼠的学习和记忆损伤。在本研究中，通过醋酸诱导扭体试验以及利用Y迷宫中的自发交替行为表现和一步下降型被动回避试验进行的东莨菪碱诱导的记忆损伤试验，对KT-95的作用进行了研究。在行为试验前30分钟，给雄性ddY小鼠皮下注射KT-95（0.24 - 2.35微摩尔/千克）。在扭体试验中，KT-95（2.35微摩尔/千克）的抗伤害感受作用被脑室内注射的nor-BNI（4.9纳摩尔/小鼠）完全拮抗，但皮下注射纳洛酮（3.05微摩尔/千克）则无此作用。KT-95显著改善了东莨菪碱（1.65微摩尔/千克，皮下注射）诱导的自发交替行为损伤。KT-95的改善作用未被nor-BNI拮抗，但几乎完全被选择性σ-受体拮抗剂N,N-二丙基-2-[4-甲氧基-3-(2-苯氧基)-苯基]-乙胺盐酸盐（NE-100，2.6微摩尔/千克，腹腔注射）拮抗。在被动回避试验中，KT-95也显著改善了东莨菪碱诱导的学习和记忆损伤，尽管作用是部分性的。单独给予KT-95可诱导学习和记忆损伤。KT-95诱导的损伤未被纳洛酮、纳曲吲哚、nor-BNI或NE-100拮抗，表明这种损伤并非由阿片受体刺激所致。这些结果提示，尽管KT-95诱导的抗伤害感受作用是由κ-阿片受体介导的，但KT-95诱导的对东莨菪碱诱导的记忆损伤的改善主要通过σ-受体介导，部分通过κ-阿片受体介导。
