Ito Mina, Nagai Taku, Mizoguchi Hiroyuki, Fukakusa Ayumi, Nakanishi Yutaka, Kamei Hiroyuki, Nabeshima Toshitaka, Takuma Kazuhiro, Yamada Kiyofumi
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
J Neurochem. 2007 Jun;101(5):1392-9. doi: 10.1111/j.1471-4159.2006.04423.x. Epub 2007 Feb 5.
We have previously demonstrated that tissue plasminogen activator (tPA)-plasmin system participates in the rewarding effect of morphine, by regulating dopamine release in the nucleus accumbens (NAc). However, it is unclear how plasmin increases the morphine-induced release of dopamine and hyperlocomotion. In the present study we investigated whether protease activated receptor-1 (PAR-1) is involved in the regulation of acute morphine-induced dopamine release by the tPA-plasmin system. Morphine significantly but transiently increased extracellular tPA activity in the NAc, which was completely blocked by naloxone. Microinjection of a PAR-1 antagonist, (tyr(-1))-thrombin receptor activating peptide 7, into the NAc significantly reduced morphine-induced dopamine release in the NAc and hyperlocomotion although the treatment had no effect on basal dopamine release and spontaneous locomotor activity. Furthermore, the PAR-1 antagonist blocked the ameliorating effect of plasmin on the defect of morphine-induced dopamine release in the NAc of tPA-deficient mice. In contrast, intracerebroventricular injection of the PAR-1 antagonist had no effect on the antinociceptive effects of morphine in mice. These results suggest that PAR-1 is a target for the tPA-plasmin system in the regulation of acute morphine-induced dopamine release in the NAc.
我们之前已经证明，组织型纤溶酶原激活物（tPA）-纤溶酶系统通过调节伏隔核（NAc）中的多巴胺释放，参与吗啡的奖赏效应。然而，尚不清楚纤溶酶如何增加吗啡诱导的多巴胺释放和运动亢进。在本研究中，我们调查了蛋白酶激活受体-1（PAR-1）是否参与tPA-纤溶酶系统对急性吗啡诱导的多巴胺释放的调节。吗啡显著但短暂地增加了NAc中的细胞外tPA活性，这被纳洛酮完全阻断。向NAc中微量注射PAR-1拮抗剂（tyr(-1)）-凝血酶受体激活肽7，显著降低了吗啡诱导的NAc中多巴胺释放和运动亢进，尽管该处理对基础多巴胺释放和自发运动活性没有影响。此外，PAR-1拮抗剂阻断了纤溶酶对tPA缺陷小鼠NAc中吗啡诱导的多巴胺释放缺陷的改善作用。相反，脑室内注射PAR-1拮抗剂对小鼠吗啡的镇痛作用没有影响。这些结果表明，PAR-1是tPA-纤溶酶系统在调节急性吗啡诱导的NAc中多巴胺释放的靶点。
