RT Journal Article
SR Electronic
T1 Stimulation of δ Opioid Receptor and Blockade of Nociceptin/Orphanin FQ Receptor Synergistically Attenuate Parkinsonism
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12953
OP 12962
DO 10.1523/JNEUROSCI.4677-13.2014
VO 34
IS 39
A1 Omar S. Mabrouk
A1 Riccardo Viaro
A1 Mattia Volta
A1 Ada Ledonne
A1 Nicola Mercuri
A1 Michele Morari
YR 2014
UL http://www.jneurosci.org/content/34/39/12953.abstract
AB 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.