Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism.
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.
Viaro
Riccardo
R
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.
Sanchez-Pernaute
Rosario
R
Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital, Belmont, Massachusetts, USA; Harvard Medical School, Belmont, Massachusetts, USA.
Marti
Matteo
M
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.
Trapella
Claudio
C
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Ferrara, Italy.
Isacson
Ole
O
Neuroregeneration Laboratories, Center for Neuroregeneration Research, McLean Hospital, Belmont, Massachusetts, USA; Harvard Medical School, Belmont, Massachusetts, USA.
Morari
Michele
M
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.
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
D001562:Benzimidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor