title: Stimulation of δ opioid receptor and blockade of nociceptin/orphanin FQ receptor synergistically attenuate parkinsonism.
abstract: δ opioid peptide (DOP) receptors are considered a therapeutic target in Parkinson's disease, although the use of DOP agonists may be limited by side effects, including convulsions. To circumvent this issue, we evaluated whether blockade of nociceptin/orphanin FQ (N/OFQ) tone potentiated the antiparkinsonian effects of DOP agonists, thus allowing for reduction of their dosage. Systemic administration of the N/OFQ receptor (NOP) antagonist J-113397 [(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one] and the DOP receptor agonist SNC-80 [(+)-4-[(αR)-α-(2S,5R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide] revealed synergistic attenuation of motor deficits in 6-hydroxydopamine hemilesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. In this model, repeated administration of the combination produced reproducible antiparkinsonian effects and was not associated with rescued striatal dopamine terminals. Microdialysis studies revealed that either systemic administration or local intranigral perfusion of J-113397 and SNC-80 led to the enhancement of nigral GABA, reduction of nigral Glu, and reduction of thalamic GABA levels, consistent with the view that NOP receptor blockade and DOP receptor stimulation caused synergistic overinhibition of nigro-thalamic GABA neurons. Whole-cell recording of GABA neurons in nigral slices confirmed that NOP receptor blockade enhanced the DOP receptor-induced effect on IPSCs via presynaptic mechanisms. Finally, SNC-80 more potently stimulated stepping activity in mice lacking the NOP receptor than wild-type controls, confirming the in vivo occurrence of an NOP-DOP receptor interaction. We conclude that endogenous N/OFQ functionally opposes DOP transmission in substantia nigra reticulata and that NOP receptor antagonists might be used in combination with DOP receptor agonists to reduce their dosage while maintaining their full therapeutic efficacy.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience and.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Mabrouk
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Section of Human Physiology, University of Ferrara, 44121 Ferrara, Italy, Department of Robotics, Brain, and Cognitive Sciences, Italian Institute of Technology, 16163 Genoa, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Viaro
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience and.
authors.forename: Mattia
authors.initials: M
authors.lastname: Volta
authors.affiliation: Department of System Medicine, Neurophysiopathology, University of Rome "Tor Vergata," 00133 Rome, Italy, and Foundation S. Lucia, Institute for Inpatient Treatment and Scientific Studies, Laboratory of Experimental Neurology, 00143 Rome Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Ledonne
authors.affiliation: Department of System Medicine, Neurophysiopathology, University of Rome "Tor Vergata," 00133 Rome, Italy, and Foundation S. Lucia, Institute for Inpatient Treatment and Scientific Studies, Laboratory of Experimental Neurology, 00143 Rome Italy.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0001-6700-7491
authors.initials: N
authors.lastname: Mercuri
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience and m.morari@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D003342:Corpus Striatum / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D004357:Drug Synergism; D005973:Glutamine / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials; D008124:Locomotion; D020267:MPTP Poisoning / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; C402921:J 113397; D010879:Piperazines; D010880:Piperidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D005973:Glutamine; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D005680:gamma-Aminobutyric Acid; D000094942:Nociceptin Receptor
keywords: SNC-80; delta opioid receptor; microdialysis; nociceptin/orphanin FQ; opioid interactions; substantia nigra