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The Journal of Neuroscience, July 28, 2004, 24(30):6659-6666; doi:10.1523/JNEUROSCI.0987-04.2004

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Behavioral/Systems/Cognitive
Blockade of Nociceptin/Orphanin FQ Receptor Signaling in Rat Substantia Nigra Pars Reticulata Stimulates Nigrostriatal Dopaminergic Transmission and Motor Behavior

Matteo Marti,¹ Flora Mela,¹ Carlo Veronesi,² Remo Guerrini,³ Severo Salvadori,³ Mauro Federici,⁴ Nicola B. Mercuri,⁴ Anna Rizzi,¹ Gianfranco Franchi,² Lorenzo Beani,¹ Clementina Bianchi,¹ and Michele Morari¹

¹Department of Experimental and Clinical Medicine, Section of Pharmacology, and Neuroscience Center, ²Department of Biomedical Sciences and Advanced Therapies, Section of Human Physiology, and ³Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy, and ⁴Instituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00179 Rome, Italy

A multidisciplinary approach was followed to investigate whether the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) regulates the nigrostriatal dopaminergic pathway and motor behavior. Nigrostriatal dopaminergic cells, which express N/OFQ peptide (NOP) receptors, are located in the substantia nigra pars compacta and extend their dendrites in the substantia nigra pars reticulata, thereby modulating the basal ganglia output neurons. In vitro electrophysiological recordings demonstrated that N/OFQ hyperpolarized the dopaminergic cells of the substantia nigra pars compacta and inhibited their firing activity. In vivo dual-probe microdialysis showed that N/OFQ perfused in the substantia nigra pars reticulata reduced dopamine release in the ipsilateral striatum, whereas UFP-101 ([Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ(1-13)-NH₂) (a selective NOP receptor peptide antagonist) stimulated it. N/OFQ microinjected in the substantia nigra pars reticulata impaired rat performance on a rotarod apparatus, whereas UFP-101 enhanced it. Electromyography revealed that N/OFQ and UFP-101 oppositely affected muscle tone, inducing relaxation and contraction of triceps, respectively. The selective NOP receptor nonpeptide antagonist J-113397 (1-[3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one), either injected intranigrally or given systemically, also elevated striatal dopamine release and facilitated motor activity, confirming that these effects were caused by blockade of endogenous N/OFQ signaling. The inhibitory role played by endogenous N/OFQ on motor activity was additionally strengthened by the finding that mice lacking the NOP receptor gene outperformed wild-type mice on the rotarod. We conclude that NOP receptors in the substantia nigra pars reticulata, activated by endogenous N/OFQ, drive a physiologically inhibitory control on motor behavior, possibly via modulation of the nigrostriatal dopaminergic pathway.

Key words: dopamine release; J-113397; substantia nigra; motor activity; UFP-101; microdialysis; nociceptin/orphanin FQ; N/OFQ

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Received March 17, 2004; revised May 25, 2004; accepted May 25, 2004.

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]

				M. Marti, C. Trapella, R. Viaro, and M. Morari The Nociceptin/Orphanin FQ Receptor Antagonist J-113397 and L-DOPA Additively Attenuate Experimental Parkinsonism through Overinhibition of the Nigrothalamic Pathway J. Neurosci., February 7, 2007; 27(6): 1297 - 1307. [Abstract] [Full Text] [PDF]

				M. Marti, F. Mela, M. Fantin, S. Zucchini, J. M. Brown, J. Witta, M. Di Benedetto, B. Buzas, R. K. Reinscheid, S. Salvadori, et al. Blockade of Nociceptin/Orphanin FQ Transmission Attenuates Symptoms and Neurodegeneration Associated with Parkinson's Disease J. Neurosci., October 19, 2005; 25(42): 9591 - 9601. [Abstract] [Full Text] [PDF]

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