Nociceptin/orphanin FQ receptor agonists attenuate L-DOPA-induced dyskinesias

Matteo Marti (1) , Donata Rodi (1) , Q. Li (2) , Remo Guerrini (3) , Stefania Fasano (4) , Ilaria Morella (4) , Alessandro Tozzi (5) , Riccardo Brambilla (4) , Paolo Calabresi (5) , Michele Simonato (6) , Erwan Bezard (7) , Michele Morari (8)

1 SVeB - Department of Life Sciences and Biotechnology (SVeB)
2 Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China
3 Department of Pharmaceutical Sciences
4 Institute of Experimental Neurology
5 Clinica Neurologica
6 Department of Clinical and Experimental Medicine (Section of Pharmacology) and Neuroscience Center
7 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
8 Department of Medical Sciences

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.

Domaines: Neurosciences

Matteo Marti, Donata Rodi, Q. Li, Remo Guerrini, Stefania Fasano, et al.. Nociceptin/orphanin FQ receptor agonists attenuate L-DOPA-induced dyskinesias. Journal of Neuroscience, 2012, 32 (46), pp.16106-16119. ⟨10.1523/JNEUROSCI.6408-11.2012⟩. ⟨hal-01053293⟩