Antiparkinson potential of δ-opioid receptor agonists
Antiparkinson potential of δ-opioid receptor agonists
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DOI：
10.1016/s0014-2999(00)00209-0
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发表时间：
2000-05-19
影响因子：
5
通讯作者：
Cross, AJ
中科院分区：
文献类型：
--
作者：
Hudzik, TJ;Howell, A;Cross, AJ
δ-阿片受体以非常高的浓度存在于纹状体和上覆皮层中，被认为涉及许多过程，包括镇痛、情绪、奖赏、神经元兴奋性的调节和神经递质释放的改变。鉴于δ阿片受体在脑运动回路中的定位，我们认为研究δ阿片受体激动剂的抗帕金森病潜力是有意义的。大鼠给予单侧6-羟基多巴胺损伤的黑质纹状体束，恢复后，进行旋转活动测试。甲磺酸托那佐辛是一种具有μ受体拮抗剂特性的非肽类部分δ阿片受体激动剂。托那佐辛（0.1-10 mg/kg）诱发剂量相关的同侧旋转，与未损伤侧多巴胺能功能增强一致。选择性δ阿片受体拮抗剂纳曲吲哚可阻断托那佐辛诱发的旋转，提示该作用是由δ阿片受体介导的。完全δ-阿片受体激动剂（+）-4-[9-α-R）-α-（2S，5 RO-4-烯丙基-2，5-二甲基-1-哌嗪基-1）-3-甲氧基苄基]-N，N-二乙基苯甲酰胺（SNC-80）产生对侧和同侧旋转。托那佐辛还增强了L-3，4-二羟基苯丙氨酸（L-DOPA）对利血平诱导的运动活动抑制的作用。还证实了托那佐辛和SNC-80对μ-、κ-和δ-阿片受体的结合亲和力和效力，并与标准品进行了比较。这些数据表明与δ-阿片受体相互作用的药物的治疗潜力，并表明托那佐辛和SNC-80的活性存在一些差异。(C)2000 Elsevier Science B. V.保留所有权利。
delta-Opioid receptors, present in very high concentrations in striatum and overlying cortex, are thought to be involved in a number of processes, including analgesia, mood, reward, modulation of neuronal excitability, and alterations in neurotransmitter release. Given the localization of the receptors in motor circuits in brain, we thought it of interest to study the antiparkinson potential of delta-opioid receptor agonists. Rats were given unilateral 6-hydroxydopamine lesions of the nigrostriatal tract, and following recovery, were tested for rotational activity. Tonazocine mesylate is a nonpeptide, partial delta-opioid receptor agonist with mu-receptor antagonist properties. Tonazocine (0.1-10 mg/kg) evoked a dose-related, ipsilateral rotation, consistent with augmentation of dopaminergic function on the unlesioned side. The rotation evoked by tonazocine was blocked by the selective delta-opioid receptor antagonist naltrindole, suggesting that the effect was mediated by delta-opioid receptors. The full delta-opioid receptor agonist (+)-4-[9-alpha-R)-alpha-(2S,5RO-4-allyl-2,5-dimethyl-1-piperaziny-1)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC-80) produced both contralateral and ipsilateral rotation. Tonazocine additionally augmented the effects of L-3,4 dihydroxyphenylalanine (L-DOPA) on reserpine-induced suppression of motor activity. Binding affinities and efficacies of tonazocine and SNC-80 against mu-, kappa-, and delta-opioid receptors were also confirmed and compared to standards. These data suggest therapeutic potential of agents interacting with delta-opioid receptors, and indicate some differences in the activities of tonazocine and SNC-80. (C) 2000 Elsevier Science B.V. All rights reserved.