Title

 

Authors

M. Marti (1), R. Guerrini (2), D. Rodi  (1), L. Qin (4) and M. Simonato (1), E. Bezard (3,4) and  M. Morari (1)
 
(1) Dept. of Experimental and Clinical Medicine, Sect. of Pharmacology, and Neurosci. Centre, University of Ferrara, Italy.
(2) Dept. of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Italy.
(3) Université Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France.
(4) Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China.

 

Abstract

Nociceptin/Orphanin FQ (N/OFQ), the endogenous ligand of the N/OFQ peptide (NOP) receptor, regulates motor, cognitive and affective behaviour in physio-pathological conditions. In particular, preclinical and clinical evidence established a link between N/OFQ and Parkinson’s disease (PD). An increase in peptide expression was found in the brain of parkinsonian rodents, and abnormally elevated N/OFQ levels were found in the SNr of 6-OHDA hemilesioned rats and  as well as in the CSF of PD patients. Increase in N/OFQ transmission contributes to parkinsonian hypokinesia since NOP receptor antagonists reversed parkinsonism in animal models of PD. Mechanistic studies revealed that the antiparkinsonian effect of NOP receptor antagonists is accomplished through modulation of the nigral output, in particular through resetting of excitatory and inhibitory inputs converging onto nigro-thalamic neurons. Interestingly, NOP receptor antagonists were also found to synergize with L-3,4 dihydroxyphenylalanine (L-DOPA) in attenuating parkinsonism in rodents and nonhuman primates, suggesting that combination therapy may offer the advantage to reduce L-DOPA dosage, thereby delaying the onset of side-effects associated with chronic therapy. Among these, the development of involuntary choreo-dystonic movements, termed dyskinesias, represent a disabling complication that reduces the clinical response and the patient quality of life. A preliminary study showed that NOP receptor agonists reduced dyskinesias in rats and the antidyskinetic effect was associated with a full motor recovery on the rotarod.  In the present follow-up study we evaluate whether NOP receptor agonists (the peptide N/OFQ and the non peptide Ro 65-6570) and antagonists (the peptide UFP-101 and the non peptide J-113397) affect abnormal involuntary movement (AIM) expression in dyskinetic rats. Moreover, we performed local injections of NOP receptor agonists and antagonists in striatum and SNr to investigate the brain area involved in their anti- or pro-dyskinetic effects, respectively. Autoradiography was employed to study whether the dyskinetic conditions was associated with changes in NOP receptor binding in brain areas relevant to motor control (motor cortex, striatum, subthalamic nucleus, substantia nigra). Microdialysis coupled to behavioral scoring allowed to investigate the impact of antidyskinetic doses of NOP receptor agonist on the nigro-thalamic transmission in dyskinetic rats, as revealed by changes in GABA and glutamate (GLU) levels in SNr and ipsilateral ventro-medial thalamus (VMTh). Finally, the proof of efficacy of a NOP receptor agonist in a nonhuman primate model of dyskinesia was provided. The study showed that NOP receptor stimulation both in DLS and SNr reduced L-DOPA-induced dyskinesias in rat, pointing out that stimulation of NOP receptors in the striatum is more effective in reducing dyskinesias than that in SNr. This effect is probably due to the increased expression of NOP receptors in the striatum of dyskinetic rats compared with control rats as evidenced by the autoradiographic study. The antidyskinetic effect of NOP receptor agonists is associated with a reduction of GABA release in the SNr and normalization of nigro-thalamic GABAergic transmission, suggesting that NOP receptor stimulation reduced dyskinesias possibly slowing the hyperactivity of striato-nigral GABAergic pathway. The present study demonstrates for the first time that NOP receptor blockade in SNr (slightly) worsens LID whereas NOP receptor stimulation in striatum palliates it. Since the antidyskinetic observed in rodents was also replicated in a nonhuman primate model of LID, we propose NOP receptor agonists as a novel therapeutic approach to LID.