title: Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson's disease.
abstract: Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine-hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson's disease. In this study, we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine-hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson's disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (-20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be approximately 3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson's disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.forename: Silvio
authors.initials: S
authors.lastname: Sarubbo
authors.forename: Francesco
authors.initials: F
authors.lastname: Latini
authors.forename: Michele
authors.initials: M
authors.lastname: Cavallo
authors.forename: Roberto
authors.initials: R
authors.lastname: Eleopra
authors.forename: Sara
authors.initials: S
authors.lastname: Biguzzi
authors.forename: Christian
authors.initials: C
authors.lastname: Lettieri
authors.forename: Carlo
authors.initials: C
authors.lastname: Conti
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchini
authors.forename: Rocco
authors.initials: R
authors.lastname: Quatrale
authors.forename: Mariachiara
authors.initials: M
authors.lastname: Sensi
authors.forename: Sanzio
authors.initials: S
authors.lastname: Candeletti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Romualdi
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006220:Haloperidol / Q000627:therapeutic use; D006801:Humans; D008297:Male; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D018847:Opioid Peptides / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult; D000097629:Nociceptin
chemical_list: D018663:Adrenergic Agents; D014150:Antipsychotic Agents; D006220:Haloperidol; D018847:Opioid Peptides; D016627:Oxidopamine; D000097629:Nociceptin