Nagai Taku, Nabeshima Toshitaka, Takuma Kazuhiro, Yamada Kiyofumi
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Nihon Arukoru Yakubutsu Igakkai Zasshi. 2006 Feb;41(1):23-30.
Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin. The tPA-plasmin system plays a role in synaptic plasticity and remodeling. In this review, we focused on the role of tPA-plasmin system in the rewarding effect of morphine. A single morphine treatment induced tPA mRNA and protein expression in a naloxone-sensitive manner, which was associated with an increase in the enzyme activity in the nucleus accumbens (NAc). The acute effect of morphine in inducing tPA expression was diminished after repeated administration. No differences were observed in the morphine-induced antinociceptive effect between wild-type and tPA knockout (tPA-/-) mice. Morphine-induced conditioned place preference and hyperlocomotion were significantly reduced in tPA-/- and pLg-/- mice, being accompanied by a loss of morphine-induced dopamine release in the NAc. Microinjection of either exogenous tPA or plasmin into the NAc significantly potentiated morphine-induced dopamine release in the NAc of ICR mice. In contrast, plasminogen activator inhibitor-1 (PAI-1) dose-dependently reduced morphine-induced dopamine release. Furthermore, the defect of morphine-induced dopamine release and hyperlocomotion in tPA-/- mice was reversed by microinjections of either exogenous tPA or plasmin into the NAc. Our findings demonstrate a novel function of the tPA-plasmin system in regulating dopamine release in the NAc, which is involved in the morphine reward.
组织型纤溶酶原激活物（tPA）是一种丝氨酸蛋白酶，可催化纤溶酶原（plg）转化为纤溶酶。tPA-纤溶酶系统在突触可塑性和重塑中发挥作用。在本综述中，我们重点关注tPA-纤溶酶系统在吗啡奖赏效应中的作用。单次吗啡处理以纳洛酮敏感的方式诱导tPA mRNA和蛋白表达，这与伏隔核（NAc）中酶活性的增加有关。重复给药后，吗啡诱导tPA表达的急性效应减弱。野生型和tPA基因敲除（tPA-/-）小鼠在吗啡诱导的镇痛作用上未观察到差异。tPA-/-和pLg-/-小鼠中吗啡诱导的条件性位置偏爱和运动亢进显著降低，同时伴有NAc中吗啡诱导的多巴胺释放减少。向ICR小鼠的NAc中微量注射外源性tPA或纤溶酶可显著增强NAc中吗啡诱导的多巴胺释放。相反，纤溶酶原激活物抑制剂-1（PAI-1）剂量依赖性地降低吗啡诱导的多巴胺释放。此外，向NAc中微量注射外源性tPA或纤溶酶可逆转tPA-/-小鼠中吗啡诱导的多巴胺释放缺陷和运动亢进。我们的研究结果证明了tPA-纤溶酶系统在调节NAc中多巴胺释放方面的新功能，这与吗啡奖赏有关。
