Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively
Endomorphin-2 and endomorphin-1 promote the extracellular amount of accumbal dopamine via nonopioid and mu-opioid receptors, respectively
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DOI：
10.1038/sj.npp.1300804
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发表时间：
2006-02-01
影响因子：
7.6
通讯作者：
Cools, AR
中科院分区：
文献类型：
--
作者：
Okutsu, H;Watanabe, S;Cools, AR
已知中脑核（NAc）中μ-阿片受体的激活增加大鼠中脑多巴胺流出。内吗啡肽-2（Tyr-Pro-Phe-Phe-NH 2; EM-2）和内吗啡肽-1（Tyr-Pro-Trp-Phe-NH 2; EM-1）被认为是μ-阿片受体的内源性配体。由于EM-2和EM-1改变自由活动大鼠脑细胞外多巴胺水平的能力尚未被研究，本研究使用微透析技术进行，该技术允许以5分钟的时间分辨率在线监测细胞外多巴胺。（5，25，和50 nmol）产生了剂量依赖性增加的多巴胺水平。EM-2（50 nmol）和EM-1（25和50 nmol）诱导的多巴胺外排被废除的tetrodotoxin（2 μ M）的脑内灌注。脑内灌注μ-阿片受体拮抗剂CTOP（D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH_2; 3 nmol）不能影响EM-2（50 nmol）诱导的多巴胺释放，而它显著抑制EM-1（25和50 nmol）诱导的多巴胺释放。全身给予假定的μ 1-阿片受体拮抗剂纳洛嗪（15 mg/kg，腹腔内（i. p.），在开始灌注前24小时给予）。全身施用非特异性阿片受体拮抗剂纳洛酮（lmg/kg，i. p.的情况下，在开始灌注前10或20分钟给予）也不能影响EM-2（50 nmol）诱导的多巴胺流出，而它显著抑制EM-1（25和50 nmol）诱导的多巴胺流出。本研究表明，脑内注射EM-2和EM-1通过完全不同的机制增加脑内多巴胺流出。它的结论是，EM-2的效果是不介导的阿片受体相反，EM-1的效果是通过μ 1-阿片受体介导的NAC。
Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH2; EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)- and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 mu M). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2; 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 ( 25 and 50 nmol)- induced dopamine release. The EM-1 ( 50 nmol)- induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine ( 15 mg/kg, intraperitoneally ( i. p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone ( 1 mg/kg, i. p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 ( 50 nmol)- induced dopamine efflux, whereas it significantly inhibited the EM-1 ( 25 and 50 nmol)- induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.