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The Journal of Neuroscience, October 19, 2005, 25(42):9591-9601; doi:10.1523/JNEUROSCI.2546-05.2005

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Neurobiology of Disease
Blockade of Nociceptin/Orphanin FQ Transmission Attenuates Symptoms and Neurodegeneration Associated with Parkinson's Disease

Matteo Marti,¹ Flora Mela,¹ Martina Fantin,¹ Silvia Zucchini,¹ Jeffrey M. Brown,⁴ Jassir Witta,⁴ Manuela Di Benedetto,³ Beata Buzas,⁴ Rainer K. Reinscheid,⁵ Severo Salvadori,² Remo Guerrini,² Patrizia Romualdi,³ Sanzio Candeletti,³ Michele Simonato,¹ Brian M. Cox,⁴ and Michele Morari¹

¹Department of Experimental and Clinical Medicine, Section of Pharmacology, and Neuroscience Center, and ²Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy, ³Department of Pharmacology, University of Bologna, 40126 Bologna, Italy, ⁴Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, and ⁵Department of Pharmacology, University of California, Irvine, Irvine, California 92697

The opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are expressed in the substantia nigra (SN), a brain area containing dopamine neurons that degenerate in Parkinson's disease. Endogenous N/OFQ facilitates nigral glutamate release and inhibits nigrostriatal dopamine transmission and motor behavior. Here, we present evidence suggesting that endogenous N/OFQ may contribute to Parkinson's disease. Pharmacological blockade of the SN N/OFQ-NOP receptor system attenuated parkinsonian-like akinesia/hypokinesia in 6-hydroxydopamine hemilesioned or haloperidol-treated rats, whereas deletion of the NOP receptor gene conferred mice partial protection from haloperidol-induced motor depression. The antiparkinsonian action of NOP receptor antagonists was associated with reduction of glutamate release in the SN. In 6-hydroxydopamine hemilesioned rats, enhancement of N/OFQ expression and release was detected in the lesioned compared with the unlesioned SN, indicating that parkinsonism may be associated with overactivation of the N/OFQ-NOP receptor system in the SN. Finally, deletion of the N/OFQ gene conferred mice partial protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of SN dopamine neurons. Based on these data, we propose that NOP receptor antagonists may represent a novel approach for combined (symptomatic and neuroprotective) therapy of Parkinson's disease.

Key words: J-113397; microdialysis; neuroprotection; nociceptin; Parkinson's disease; UFP-101

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Received Nov 26, 2003; revised August 30, 2005; accepted September 1, 2005.

This article has been cited by other articles:

				A. Rizzi, E. C. Gavioli, G. Marzola, B. Spagnolo, S. Zucchini, R. Ciccocioppo, C. Trapella, D. Regoli, and G. Calo J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 968 - 974. [Abstract] [Full Text] [PDF]

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