Shukla V K, Prasad J A, Lemaire S
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
J Pharmacol Exp Ther. 1997 Nov;283(2):604-10.
Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED50 value of 14.32 (95% confidence limits, 10.09-20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A approximately Dyn A-(1-13) > [Ala1]Dyn A-(1-13) approximately Dyn A-(2-13) > alpha-Neo-End > Dyn A-(1-8) approximately Dyn B approximately Dyn A-(2-8) >>> Dyn A-(3-8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6-10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2-13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1-13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2-0.6 nmol/mouse) of the N-methyl-D-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [3H]MK-801, to rat brain membranes, with a Ki value of 0.41 microM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [3H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [3H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2-8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.
对强啡肽（Dyn）A及相关的阿片样和非阿片样肽在小鼠中产生运动效应的能力进行了测试。给小鼠脑室内注射Dyn A可产生显著的运动效应，其特征为疯狂奔跑、跳跃、转圈和/或翻滚，半数有效剂量（ED50）值为14.32（95%置信限，10.09 - 20.32）nmol/小鼠。各种与Dyn A相关的肽和片段产生运动效应的效力顺序为：Dyn A≈Dyn A-(1 - 13)>[丙氨酸1]Dyn A-(1 - 13)≈Dyn A-(2 - 13)>α-新内啡肽>Dyn A-(1 - 8)≈强啡肽B≈Dyn A-(2 - 8)>>>Dyn A-(3 - 8)。Dyn A-(1 - 5)（或亮氨酸脑啡肽）和Dyn A-(6 - 10)在剂量高达100 nmol/小鼠时未显示运动效应。Dyn A和Dyn A-(2 - 13)的效力不受皮下注射纳洛酮（5 mg/kg）预处理的影响，但预先给予低剂量（0.2 - 0.6 nmol/小鼠）的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂右啡烷、MK-801和CPP可显著降低Dyn A-(1 - 13)（20 nmol/小鼠，脑室内注射）的运动效应。Dyn A还是苯环己哌啶受体配体[3H]MK-801与大鼠脑膜结合的强效抑制剂，抑制常数（Ki）值为0.41 μM。然而，各种与Dyn A相关的肽和片段抑制[3H]MK-801结合的效力顺序与其产生运动效应的能力不相关。另一方面，Dyn A及相关肽可显著增强竞争性NMDA拮抗剂[3H]CGP-39653与大鼠脑膜的结合，这一效应与其产生运动效应的效力密切相关（r = 0.91）。这些结果表明，Dyn A及相关肽的非阿片样运动效应取决于结构，其中Dyn A-(2 - 8)是产生运动活性的最小核心肽。此外，这些效应很可能涉及NMDA受体复合物上兴奋性氨基酸结合域的参与。
