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: Matteo Marti, Silvio Sarubbo, Francesco Latini, Michele Cavallo, Roberto Eleopra, Sara Biguzzi, Christian Lettieri, Carlo Conti, Michele Simonato, Silvia Zucchini, Rocco Quatrale, Mariachiara Sensi, Sanzio Candeletti, Patrizia Romualdi, Michele Morari
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 25 Issue 11 Pg. 1723-32 (Aug 15 2010) ISSN: 1531-8257 [Electronic] United States
• PMID: 20589874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Agents
• Antipsychotic Agents
• Opioid Peptides
• Oxidopamine
• Haloperidol

Topics

• Adrenergic Agents (toxicity)
• Adult
• Aged
• Aged, 80 and over
• Analysis of Variance
• Animals
• Antipsychotic Agents (pharmacology)
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects, physiology)
• Haloperidol (therapeutic use)
• Humans
• Male
• Microdialysis (methods)
• Middle Aged
• Opioid Peptides (cerebrospinal fluid, genetics, metabolism)
• Oxidopamine (toxicity)
• Parkinson Disease (cerebrospinal fluid, drug therapy, etiology, pathology)
• Rats
• Rats, Sprague-Dawley
• Young Adult
• Nociceptin