Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia

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Pisanò, Clarissa A.
Mercatelli, Daniela
Mazzocchi, Martina
Brugnoli, Alberto
Morella, Ilaria
Fasano, Stefania
Zaveri, Nurulain T.
Brambilla, Riccardo
O'Keeffe, Gerard W.
Neubig, Richard R.
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Wiley; British Pharmacological Society
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Background and Purpose: Regulator of G-protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l-Dopa-induced dyskinesia. Experimental Approach: HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small-molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and l-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key Results: RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403-mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l-Dopa. l-Dopa acutely up-regulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signalling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up-regulation occurring during dyskinesia expression. Linked articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit
AT-403 , CCG-203920 , Dyskinesia , L-Dopa , Nociceptin/orphanin FQ , RGS4 , Opioid
Pisanò, C.A., Mercatelli, D., Mazzocchi, M., Brugnoli, A., Morella, I., Fasano, S., Zaveri, N.T., Brambilla, R., O’Keeffe, G.W., Neubig, R.R. and Morari, M. (2023) ‘Regulator of G‐Protein Signalling 4 (Rgs4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l ‐Dopa‐induced dyskinesia’, British Journal of Pharmacology, 180(7), pp. 927–942. Available at:
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