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.
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