Nociceptin/orphanin FQ receptor antagonists reverse parkinsonism in MPTP-treated mice and non-human primates

Objective: To evaluate the ability of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) antagonist J-113397 to reverse parkinsonian-like symptoms in mice and non human primates treated with MPTP. Background: N/OFQ has been shown to inhibit nigrostriatal dopaminergic transmission and motor function (Marti et al., 2004, J Neurosci 24, 6659-6666) and to influence symptoms and neurodegeneration associated with experimental parkinsonism (Marti et al., 2005, J Neurosci 95, 9591-9601). In particular, pharmacological blockade of hyperactive N/OFQergic transmission in the substantia nigra by NOP receptor antagonists improved motor function in rats made akinetic by haloperidol or 6-OHDA lesioning. Methods: C57BL/6J mice were treated with MPTP (4x20 mg/kg i.p., 90 min apart) and motor activity evaluated by means of the bar, drag and rotarod tests (Marti et al., 2005). Seven days after MPTP, J-113397 was administered (0.01 mg/kg i.p.) and behaviour monitored at 10 and 60 min post-injection. Macaca fascicularis primates developed stable moderate-to-severe parkinsonism 4 months after i.v. administration of MPTP (6-12 mg; Parkinson Rating Scale 18-22). The effect of J-113397 (0.01 mg/kg i.m.) was evaluated by means of a PRS scale 30 min after drug administration. L-DOPA was given both in mice (10 mg/kg, i.p.) and macaques (30 mg/kg, i.m.) as a control. Results: MPTP-treated mice displayed increased time on bar, reduced number of steps and impaired performance on the rotarod compared to vehicle-injected mice. L-DOPA reversed motor deficits in all behavioural tests, its action being still evident after 60 min. J-113397 reproduced L-DOPA effects, although its action was less pronounced and short-lasting. L-DOPA also reversed parkinsonism in MPTP-treated macaques (~45% improvement compared to baseline). Again, J-113397 mimicked L-DOPA effects, although less effectively (~20%). J-113397 was most effective against hypokinesia. Conclusion: Our data suggest that endogenous N/OFQ actions contribute to motor deficits associated with MPTP administration in both mice and non human primates, and strengthen the view that NOP receptor antagonists may represent a novel therapeutic approach to Parkinson’s disease. Supported by the Michael J Fox Foundation for Parkinson’s Research.