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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。孤啡肽/孤啡肽FQ（N/OFQ）是一种阿片样神经肽，可激活G蛋白偶联受体NOP受体。我们表明，在大鼠中，表达在黑质（SN）纹状体的多巴胺能神经元上的NOP受体的激活导致黑质纹状体传递和运动行为的抑制（Marti等人，2004，J. Neurosci，24：6659-6666）。大鼠中的初步数据（Marti等人，2004，Mov Dis 19，Supp 9，P564，P703）也表明内源性N/OFQ维持帕金森病，因为NOP受体拮抗剂UFP-101和J- 113397（给予SN或全身给药）促进偏侧帕金森病大鼠的运动表现。UFP-101还减少了网状SN中氟哌啶醇诱导的僵住症并使谷氨酸释放正常化。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抗性。这些发现强烈表明，N/OFQ传输的阻断可能代表了帕金森病对症治疗的新方法，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.