Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson's disease.
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.
Marti
Matteo
M
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Sarubbo
Silvio
S
Latini
Francesco
F
Cavallo
Michele
M
Eleopra
Roberto
R
Biguzzi
Sara
S
Lettieri
Christian
C
Conti
Carlo
C
Simonato
Michele
M
Zucchini
Silvia
S
Quatrale
Rocco
R
Sensi
Mariachiara
M
Candeletti
Sanzio
S
Romualdi
Patrizia
P
Morari
Michele
M
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
D018663:Adrenergic Agents; D014150:Antipsychotic Agents; D006220:Haloperidol; D018847:Opioid Peptides; D016627:Oxidopamine; D000097629:Nociceptin