Okutsu Hiroko, Watanabe Shu, Takahashi Ichiro, Aono Yuri, Saigusa Tadashi, Koshikawa Noriaki, Cools Alexander R
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba, Japan.
Neuropsychopharmacology. 2006 Feb;31(2):375-83. doi: 10.1038/sj.npp.1300804.
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-NH(2); EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2); 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 muM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH(2); 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.
已知伏隔核（NAc）中μ-阿片受体的激活会增加大鼠伏隔核中的多巴胺外流。内吗啡肽-2（Tyr-Pro-Phe-Phe-NH₂；EM-2）和内吗啡肽-1（Tyr-Pro-Trp-Phe-NH₂；EM-1）被认为是μ-阿片受体的内源性配体。由于尚未在自由活动的大鼠中研究EM-2和EM-1改变伏隔核细胞外多巴胺水平的能力，因此进行了本研究，使用微透析技术以5分钟的时间分辨率在线监测细胞外多巴胺。向NAc中注入EM-2或EM-1（5、25和50 nmol）25分钟会使伏隔核多巴胺水平呈剂量依赖性增加。伏隔核内灌注河豚毒素（2 μM）可消除EM-2（50 nmol）和EM-1（25和50 nmol）诱导的多巴胺外流。伏隔核内灌注μ-阿片受体拮抗剂CTOP（D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH₂；3 nmol）未能影响EM-2（50 nmol）诱导的多巴胺释放，而它显著抑制了EM-1（25和50 nmol）诱导的多巴胺释放。在开始灌注前24小时腹腔注射（i.p.）推定的μ1-阿片受体拮抗剂纳洛酮嗪（15 mg/kg）可显著降低EM-1（50 nmol）诱导的伏隔核多巴胺外流。在开始灌注前10或20分钟腹腔注射（i.p.）非特异性阿片受体拮抗剂纳洛酮（1 mg/kg）也未能影响EM-2（50 nmol）诱导的多巴胺外流，而它显著抑制了EM-1（25和50 nmol）诱导的多巴胺外流。本研究表明，向伏隔核内注入EM-2和EM-1通过完全不同的机制增加伏隔核多巴胺外流。得出的结论是，与EM-1通过NAc中的μ1-阿片受体介导的作用相反，EM-2的作用不是通过阿片受体介导的。
