title: Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism.
abstract: Endogenous nociceptin/orphanin FQ (N/OFQ) inhibits the activity of dopamine neurons in the substantia nigra and affects motor behavior. In this study we investigated whether a N/OFQ receptor (NOP) antagonist, J-113397, can modify movement in naive mice and nonhuman primates and attenuate motor deficits in MPTP-treated parkinsonian animals. J-113397 facilitated motor activity in naïve mice at low doses (0.1-1 mg/kg) and inhibited it at higher ones (10 mg/kg). Likewise, in MPTP-treated mice, J-113397 reversed motor deficit at 0.01 mg/kg but worsened hypokinesia at higher doses (1 mg/kg). In naïve nonhuman primates, J-113397, ineffective up to 1 mg/kg, produced inconsistent motor improvements at 3 mg/kg. Conversely, in parkinsonian primates J-113397 (0.01 mg/kg) reversed parkinsonism, being most effective against hypokinesia. We conclude that endogenous N/OFQ modulates motor activity in mice and nonhuman primates and contributes to parkinsonian symptoms in MPTP-treated animals. NOP receptor antagonists may represent a novel approach to Parkinson's disease.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy; Neuroscience Center and Istituto Nazionale di Neuroscienze, University of Ferrara, Ferrara, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Viaro
authors.affiliation: Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital, Belmont, Massachusetts, USA; Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Rosario
authors.initials: R
authors.lastname: Sanchez-Pernaute
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy; Neuroscience Center and Istituto Nazionale di Neuroscienze, University of Ferrara, Ferrara, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital, Belmont, Massachusetts, USA; Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy; Neuroscience Center and Istituto Nazionale di Neuroscienze, University of Ferrara, Ferrara, Italy. Electronic address: m.morari@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009292:Narcotic Antagonists; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000502:physiology*; D000094942:Nociceptin Receptor
chemical_list: D001562:Benzimidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor