Delta 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-[(R)--(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