ROLE OF NOCICEPTIN/ORPHANIN FQ IN REGULATION OF MOTOR BEHAVIOR & INDUCTION OF PD

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。伤害素/孤啡肽FQ(N/OFQ)是一种阿片样神经肽，能激活G蛋白偶联受体NOP受体。我们发现，表达在黑质致密区多巴胺能神经元上的NOP受体的激活导致大鼠黑质纹状体传递和运动行为的抑制(Marti等人，2004，J.Neurosci，24：6659-6666)。在大鼠中的初步数据(Marti等人，2004年，Mov Dis19，Supp 9，P564，P703)也表明内源性N/OFQ维持帕金森病，因为一氧化氮合酶受体拮抗剂UFP-101和J-113397(注入SN或全身给药)促进了偏侧帕金森病大鼠的运动能力。UFP-101还减少了氟哌啶醇诱导的类胡萝卜素中毒，并使SN网状核的谷氨酸释放正常化。此外，与野生型小鼠相比，缺乏NOP受体基因的小鼠对氟哌啶醇表现出更大的抵抗力。这些发现有力地表明，阻断N/OFQ传递可能代表了对症治疗帕金森S病的一种新方法，并将在灵长类动物模型中进行研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that activates a G-protein coupled receptor, the NOP receptor. We showed that activation of NOP receptors expressed onto dopaminergic neurons of the substantial nigra (SN) compacta leads to inhibition of the nigrostriatal transmission and motor behavior in rats (Marti et al., 2004, J. Neurosci, 24: 6659-6666). Preliminary data in rats (Marti et al., 2004, Mov Dis19, Supp 9, P564, P703) also indicate that endogenous N/OFQ sustains parkinsonism, as NOP receptor antagonists UFP-101 and J- 113397 (either given into the SN or administered systemically) facilitated motor performance of hemiparkinsonian rats. UFP-101 also reduced haloperidol-induced catalepsy and normalized glutamate release in the SN reticulata. Furthermore, mice lacking the NOP receptor gene displayed greater resistance to haloperidol compared to wild-type mice. These findings strongly suggest that blockade of N/OFQ transmission may represent a novel approach for symptomatic therapy of Parkinson¿s disease and will be investigated in a primate model.