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: Riccardo Viaro, Rosario Sanchez-Pernaute, Matteo Marti, Claudio Trapella, Ole Isacson, Michele Morari
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 30 Issue 3 Pg. 430-438 (Jun 2008) ISSN: 1095-953X [Electronic] United States
• PMID: 18413287 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• J 113397
• Narcotic Antagonists
• Piperidines
• Receptors, Opioid
• Nociceptin Receptor

Topics

• Animals
• Benzimidazoles (pharmacology, therapeutic use)
• MPTP Poisoning (metabolism, physiopathology, prevention & control)
• Macaca fascicularis
• Male
• Mice
• Mice, Inbred C57BL
• Motor Skills (drug effects, physiology)
• Narcotic Antagonists
• Piperidines (pharmacology, therapeutic use)
• Receptors, Opioid (physiology)
• Nociceptin Receptor