@article {Marti16106, author = {Matteo Marti and Donata Rodi and Qin Li and Remo Guerrini and Stefania Fasano and Ilaria Morella and Alessandro Tozzi and Riccardo Brambilla and Paolo Calabresi and Michele Simonato and Erwan Bezard and Michele Morari}, title = {Nociceptin/Orphanin FQ Receptor Agonists Attenuate l-DOPA-Induced Dyskinesias}, volume = {32}, number = {46}, pages = {16106--16119}, year = {2012}, doi = {10.1523/JNEUROSCI.6408-11.2012}, publisher = {Society for Neuroscience}, abstract = {In the present study we investigated whether the neuropeptide nociceptin/orphanin FQ (N/OFQ), previously implicated in the pathogenesis of Parkinson{\textquoteright}s disease, also affects l-DOPA-induced dyskinesia. In striatal slices of naive rodents, N/OFQ (0.1{\textendash}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{\textendash}1 nmol, i.c.v.) or a synthetic N/OFQ receptor agonist given systemically (0.01{\textendash}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.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/32/46/16106}, eprint = {https://www.jneurosci.org/content/32/46/16106.full.pdf}, journal = {Journal of Neuroscience} }