title: Blockade of nociceptin/orphanin FQ transmission in rat substantia nigra reverses haloperidol-induced akinesia and normalizes nigral glutamate release.
abstract: We recently showed that pharmacological blockade of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors located in the substantia nigra stimulates the nigrostriatal dopaminergic pathway and motor behavior (Marti et al. J. Neurosci. 2004, 24, 6659-6666). To investigate whether such motor-stimulating action was dependent on functional dopaminergic transmission, the selective NOP receptor peptide antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) was microinjected into the substantia nigra reticulata of rats made cataleptic by systemic haloperidol administration. UFP-101 reduced haloperidol-induced akinesia as measured by immobility time in the bar test. UFP-101 also induced contralateral turning in cataleptic rats. To investigate the mechanisms involved in the anti-akinetic action of UFP-101, nigral glutamate release was monitored by microdialysis technique. The anti-akinetic action of UFP-101 correlated with normalization of nigral glutamate release, previously elevated by haloperidol injection. We conclude that endogenous N/OFQ in the substantia nigra sustains akinesia generated by impaired DA transmission and subthalamic nucleus overactivation. NOP receptor antagonists may be beneficial in the symptomatic therapy of parkinsonism, via normalization of subthalamonigral glutamatergic transmission.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, Neuroscience Center, University of Ferrera, Ferrera, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.forename: Flora
authors.initials: F
authors.lastname: Mela
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.forename: Clementina
authors.initials: C
authors.lastname: Bianchi
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D018492:Dopamine Antagonists; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol; D008297:Male; D017551:Microdialysis; D018847:Opioid Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism*; D000097629:Nociceptin
chemical_list: D018492:Dopamine Antagonists; D018698:Glutamic Acid; D006220:Haloperidol; D018847:Opioid Peptides; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)