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

2区 · 医学

Article

作者: Zaveri, Nurulain T. ; Morari, Michele ; Pisanò, Clarissa A. ; O'Keeffe, Gerard W. ; Brugnoli, Alberto ; Neubig, Richard R. ; Mercatelli, Daniela ; Mazzocchi, Martina ; Fasano, Stefania ; Morella, Ilaria ; Brambilla, Riccardo

Background and PurposeRegulator 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 ApproachHEK293T 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 ResultsRGS4 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 ImplicationsRGS4 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 ARTICLESThis 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 http://onlinelibrary.wiley.com.libproxy1.nus.edu.sg/doi/10.1111/bph.v180.7/issuetoc

2022-01-01·Computers in Biology and Medicine3区 · 工程技术

Impact of anatomical reverse remodelling in the design of optimal quadripolar pacing leads: A computational study

3区 · 工程技术

Article

作者: Plank, Gernot ; Strocchi, Marina ; Vigmond, Edward J ; Lee, Angela W C ; Niederer, Steven A ; Lamata, Pablo ; Rodero, Cristobal ; Rinaldi, Christopher A

Lead position is an important factor in determining response to Cardiac Resynchronization Therapy (CRT) in dyssynchronous heart failure (HF) patients. Multipoint pacing (MPP) enables pacing from multiple electrodes within the same lead, improving the potential outcome for patients. Virtual quadripolar lead designs were evaluated by simulating pacing from all combinations of 1 and 2 electrodes along the lead in each virtual patient from cohorts of HF (n = 24) and simulated reverse remodelled (RR, n = 20) patients. Electrical synchrony was assessed by the time 90% of the ventricular myocardium is activated (AT090). Optimal 1 and 2 electrode pacing configurations for AT090 were combined to identify the 4-electrode lead design that maximised benefits across all patients. LV pacing in the HF cohort in all possible single and double electrode locations reduced AT090 by 14.48 ± 5.01 ms (11.92 ± 3.51%). The major determinant of reduction in activation time was patient anatomy. Pacing with a single optimal lead design reduced AT090 more in the HF cohort than the RR cohort (12.68 ± 3.29% vs 10.81 ± 2.34%). Pacing with a single combined HF and RR population-optimised lead design achieves electrical resynchronization with near equivalence to personalised lead designs both in HF and RR anatomies. These findings suggest that although lead configurations have to be tailored to each patient, a single optimal lead design is sufficient to obtain near-optimal results across most patients. This study shows the potential of virtual clinical trials as tools to compare existing and explore new lead designs.

2022-01-01·British Journal of Pharmacology2区 · 医学

Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists

2区 · 医学

Article

作者: Sutphen, Jane C. ; Kapusta, Daniel R. ; Denys, Ian B. ; Gao, Juan ; Zaveri, Nurulain T.

Background and PurposePartial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small‐molecule NOP receptor ligands may be more suitable as therapeutic agents. This study investigated the cardiovascular and renal responses produced by the novel nonpeptide NOP agonists AT‐403, AT‐090, AT‐127, and AT‐039.Experimental ApproachChanges in mean arterial pressure (MAP), heart rate (HR), renal excretory function and occurrence of sedation and hyperphagia were determined before and after i.v. bolus injection or infusion of the NOP agonists in conscious Sprague–Dawley rats. Additional studies involving (i) measurement of renal sympathetic nerve activity (RSNA) and (ii) renal denervation were conducted to investigate the role of the renal nerves in the cardiorenal responses to AT‐039.Key ResultsBolus i.v. injection of AT‐403, AT‐090, AT‐127 and AT‐039 produced significant decreases in MAP and HR and a sodium‐sparing diuresis. AT‐403, AT‐090, and AT‐127, but not AT‐039, induced sedation and hyperphagia at all doses tested. Infusion i.v. of AT‐039 produced hypotension and aquaresis without adverse central nervous system effects or change in HR, responses that were also observed in renal denervated rats.Conclusions and ImplicationsNonpeptide NOP agonists decrease blood pressure and produce aquaresis in conscious rodents. Due to lack of sedation and hyperphagia, AT‐039 represents a novel NOP agonist that may be useful for treatment of hypertension and/or volume overload/hyponatraemic states.

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适应症	最高研发状态	国家/地区	公司	日期
焦虑症	临床前	美国	Astraea Therapeutics LLC	-
焦虑症	临床前	美国	LSU Health Sciences Center	-
抑郁症	临床前	美国	Astraea Therapeutics LLC	-
抑郁症	临床前	美国	LSU Health Sciences Center	-
疼痛	临床前	美国	Astraea Therapeutics LLC	-
疼痛	临床前	美国	LSU Health Sciences Center	-
帕金森病	临床前	美国	Astraea Therapeutics LLC	-
帕金森病	临床前	美国	LSU Health Sciences Center	-