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: Matteo Marti, Donata Rodi, Qin Li, Remo Guerrini, Stefania Fasano, Ilaria Morella, Alessandro Tozzi, Riccardo Brambilla, Paolo Calabresi, Michele Simonato, Erwan Bezard, Michele Morari
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 32 Issue 46 Pg. 16106-19 (Nov 14 2012) ISSN: 1529-2401 [Electronic] United States
• PMID: 23152595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Dyskinesia Agents
• Antiparkinson Agents
• Opioid Peptides
• Glutamic Acid
• Levodopa
• gamma-Aminobutyric Acid
• Oxidopamine

Topics

• Animals
• Anti-Dyskinesia Agents
• Antiparkinson Agents (adverse effects)
• Autoradiography
• Behavior, Animal (drug effects)
• Dyskinesia, Drug-Induced (drug therapy)
• Electrophysiological Phenomena
• Excitatory Postsynaptic Potentials (drug effects)
• Glutamic Acid (metabolism)
• Levodopa (adverse effects)
• Macaca
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microdialysis
• Microinjections
• Opioid Peptides (agonists, antagonists & inhibitors, genetics)
• Oxidopamine (toxicity)
• Postural Balance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• gamma-Aminobutyric Acid (metabolism)
• Nociceptin