Sugiyama Azusa, Nagase Hiroshi, Oka Jun-Ichiro, Yamada Mitsuhiko, Saitoh Akiyoshi
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan; Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki 305-8577, Japan.
Neuropharmacology. 2014 Apr;79:314-20. doi: 10.1016/j.neuropharm.2013.11.021. Epub 2013 Dec 12.
Recently, we reported that the δ opioid receptor (DOR) agonist KNT-127 produces anxiolytic-like effects in behaving rats. Here, we report on the roles of DOR subtypes ( DOR(1) and DOR(2)) play in mediating KNT-127-induced anxiolytic-like effects. Pretreatment with the DOR(2)-selective antagonist naltriben (NTB; 0.05mg/kg, s.c.) completely abolished KNT-127 (3.0mg/kg, s.c.)-induced anxiolytic-like effects in rats performing the elevated plus-maze task. By contrast, the DOR(1)-selective antagonist 7-benzylidenenaltrexone (BNTX; 0.5mg/kg, s.c.) produced no effect at a dose that completely blocked the antinociceptive effects of KNT-127. These findings were also supported by results from a light/dark test and open-field test. We clearly demonstrated that the DOR(2)-selective antagonist, but not the DOR(1)-selective antagonist, abolishes the anxiolytic-like effects of the DOR agonist KNT-127, suggesting different roles of these DOR subtypes in anxiety. We propose that DOR(2)-selective agonists would be good candidates for future development of anxiolytic drugs.
最近，我们报道δ阿片受体（DOR）激动剂KNT-127在行为学实验大鼠中产生抗焦虑样效应。在此，我们报告DOR亚型（DOR(1)和DOR(2)）在介导KNT-127诱导的抗焦虑样效应中所起的作用。用DOR(2)选择性拮抗剂纳曲苄（NTB；0.05mg/kg，皮下注射）预处理，可完全消除KNT-127（3.0mg/kg，皮下注射）在高架十字迷宫实验大鼠中诱导的抗焦虑样效应。相比之下，DOR(1)选择性拮抗剂7-苄叉基纳曲酮（BNTX；0.5mg/kg，皮下注射）在完全阻断KNT-127的抗伤害感受作用的剂量下没有效果。明暗箱实验和旷场实验的结果也支持了这些发现。我们明确证明，DOR(2)选择性拮抗剂而非DOR(1)选择性拮抗剂可消除DOR激动剂KNT-127的抗焦虑样效应，这表明这些DOR亚型在焦虑中具有不同作用。我们认为DOR(2)选择性激动剂有望成为未来抗焦虑药物开发的良好候选药物。
