title: Nociceptin/orphanin FQ receptor agonists attenuate L-DOPA-induced dyskinesias.
abstract: In the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson's disease, also affects L-DOPA-induced dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1-1 μm) prevented the increase of ERK phosphorylation and the loss of depotentiation of synaptic plasticity induced by the D1 receptor agonist SKF38393 in spiny neurons. In vivo, exogenous N/OFQ (0.03-1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01-1 mg/Kg) attenuated dyskinesias expression in 6-hydroxydopamine hemilesioned rats primed with L-DOPA, without causing primary hypolocomotive effects. Conversely, N/OFQ receptor antagonists worsened dyskinesia expression. In vivo microdialysis revealed that N/OFQ prevented dyskinesias simultaneously with its neurochemical correlates such as the surge of nigral GABA and glutamate, and the reduction of thalamic GABA. Regional microinjections revealed that N/OFQ attenuated dyskinesias more potently and effectively when microinjected in striatum than substantia nigra (SN) reticulata, whereas N/OFQ receptor antagonists were ineffective in striatum but worsened dyskinesias when given in SN. Quantitative autoradiography showed an increase in N/OFQ receptor binding in striatum and a reduction in SN of both unprimed and dyskinetic 6-hydroxydopamine rats, consistent with opposite adaptive changes of N/OFQ transmission. Finally, the N/OFQ receptor synthetic agonist also reduced dyskinesia expression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated dyskinetic macaques without affecting the global parkinsonian score. We conclude that N/OFQ receptor agonists may represent a novel strategy to counteract L-DOPA-induced dyskinesias. Their action is possibly mediated by upregulated striatal N/OFQ receptors opposing the D1 receptor-mediated overactivation of the striatonigral direct pathway.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, 44100 Ferrara Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.forename: Donata
authors.initials: D
authors.lastname: Rodi
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Stefania
authors.initials: S
authors.lastname: Fasano
authors.forename: Ilaria
authors.initials: I
authors.lastname: Morella
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Brambilla
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D008845:Microinjections; D018847:Opioid Peptides / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000097629:Nociceptin
chemical_list: D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D018698:Glutamic Acid; D007980:Levodopa; D018847:Opioid Peptides; D016627:Oxidopamine; D005680:gamma-Aminobutyric Acid; D000097629:Nociceptin