The non-peptidic delta opioid receptor agonist TAN-67 enhances dopamine efflux in the nucleus accumbens of freely moving rats via a mechanism that involves both glutamate and free radicals
The non-peptidic delta opioid receptor agonist TAN-67 enhances dopamine efflux in the nucleus accumbens of freely moving rats via a mechanism that involves both glutamate and free radicals
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DOI：
10.1016/j.neuroscience.2004.10.016
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Cools, AR
中科院分区：
文献类型：
--
作者：
Fusa, K;Takahashi, I;Cools, AR
已知延髓核中δ-阿片受体的激活可诱导氯巴宁外排的大量快速增加。（+/-）-TAN-67（2-甲基-4a α-（3-羟基苯基）-1，2，3，4，4a，5，12，12 a α-八氢-喹啉并[2，3，3，- g]异喹啉）是最近可获得的中枢作用的非肽类阿片受体剂。有趣的是，TAN-67的（+）对映体诱导痛觉过敏，而TAN-67的（-）对映体在小鼠中产生深刻的抗伤害感受作用;后者的作用是通过α-1受体刺激介导的。采用微透析技术，分析了TAN-67对映体改变氯巴宁体内释放的能力。比如25分钟的选择性δ-1阿片受体激动剂（D-[Pen（2，5）]-脑啡肽）DPDPE（50 nM）和δ-2阿片受体激动剂deltorphin II（50 nM），25分钟输注（-）-TAN-67（25和50 nM）和（+）-TAN-67（25和50 nM）进入丘脑核产生了类似的短暂的细胞外多巴胺水平的密切依赖性增加。将纳洛酮（lmg/kg i. p.，在给药前25分钟给予），即已知抑制由DPDPE和deltorphin II诱导的氯巴宁增加的治疗，不影响由输注TAN-67的对映体产生的多巴胺水平的瞬时增加。DPDPE和deltorphin II-引起脑内多巴胺水平升高。而不是（-YTAN-67和（+YTAN-67）。通过随后灌注河豚毒素（2 μ M）到丘脑核中消除。通过输注β-YTAN-67和β-YTAN-67产生的多巴胺水平的增加不被无Ca 2+的林格氏溶液改变。利血平（5 mg/kg i. p.，提前24小时给药）或α-甲基-对-酪氨酸（250 mg/kg腹膜内，2小时前）。利血平和a-甲基-对-酪氨酸联合处理可消除TAN-67对映体对多巴胺的作用。N* 甲基-D-天冬氨酸（NMDA）受体拮抗剂艾芬地尔（20 mg/kg，20分钟前）和MK-801（0.5 mg/kg i. p.，20分钟前）。（-）-TAN-67对多巴胺流出的作用也被自由基清除剂N-2-巯基丙酰甘油（100 mg/kg i. p.，20分钟前）。这些结果表明，TAN-67的两种对映体均增强利血平敏感性的释放。囊泡多巴胺和α-甲基-p-酪氨酸敏感。胞质多巴胺从多巴胺能神经末梢在延髓核的方式是独立的神经活动：8阿片受体的激活在这些事件中不起作用。总之，结果表明（-）-TAN-67 ran产生自由基的爆发，其进而触发谷氨酸的释放，最终通过NMDA受体的活化增强多巴胺从中脑核中的多巴胺能神经末梢的释放。(C)2005年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal cloparnine efflux. (+/-)-TAN-67 (2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-octahydro-quinolino[2,3,3,- g]isoquinoline) is a centrally acting non-peptidic 8 opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (-) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through alpha-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal cloparnine in vivo was analyzed. Like the 25-min infusion of the selective delta-1 opioid receptor agonist (D-[Pen(2,5)]-enkephalin) DPDPE (50 nM) and the delta-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (-)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient close-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of cloparnine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-incluced increase in accumbal dopamine level. but not that of (-YTAN-67 and (+YTAN-67. was eliminated by subsequently perfused tetrodotoxin (2 muM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (-YTAN-67 and (-YTAN-67 was not altered by a Ca2+-free Ringers solution. The (-)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and a-methyl-para-tyrosine. The (-)-TAN-indured dopamine efflux was significantly reduced by the N*methyl-D-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (-)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glydne (100 mg/kg i.p., 20 min before). These results show that both enantiomers of TAN-67 enhance the release of reserpine sensitive. vesicular dopamine and alpha-methyl-p-tyrosine sensitive. cytosolic dopamine from dopaminergic nerve terminals in the nucleus accumbens in a way that is independent of neural activity: activation of 8 opioid receptors plays no role in these events. All together, the results suggest that (-)-TAN-67 ran generate a burst of free radicals that in turn trigger a release of glutamate that ultimately via activation of NMDA receptors enhances the release of dopamine from dopaminergic nerve terminals in the nucleus accumbens. (C) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.