Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands

Viaro, Riccardo; Calcagno, Mariangela; Marti, Matteo; Borrelli, Emiliana; Morari, Michele

doi:10.1016/j.neuropharm.2013.04.046

Cited by 14 publications

(18 citation statements)

References 49 publications

(122 reference statements)

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“…the bar, drag and rotarod tests, were used as described [43, 84, 85]. Experimenters were unaware of genotype and treatments.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, the fixed-speed rotarod test integrates different motor parameters such as motor coordination, gait ability, balance, muscle tone and motivation to run. Mice were tested over a wide range of increasing speeds (0–55 rpm; 5 rpm steps, increased every 180 s) on a rotating rod (diameter of the cylinder 8 cm) and the total time spent on the rod was recorded [84, 85]…”

Section: Methodsmentioning

confidence: 99%

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Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Longo

Mercatelli

Novello

et al. 2017

acta neuropathol commun

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls. In vivo striatal dopamine release was insensitive to the LRRK2 inhibitor Nov-LRRK2-11, and was elevated by the membrane dopamine transporter blocker GBR-12783. However, G2019S knock-in mice showed a blunted neurochemical and motor activation response to GBR-12783 compared to wild-type controls. Western blot and dopamine uptake analysis revealed an increase in dopamine transporter levels and activity in the striatum of 12-month-old G2019S KI mice. This phenotype correlated with a reduction in vesicular monoamine transporter 2 levels and an enhancement of vesicular dopamine uptake, which was consistent with greater resistance to reserpine-induced hypolocomotion. These changes were not observed in 3-month-old mice. Finally, Western blot analysis revealed no genotype difference in striatal levels of endogenous α-synuclein or α-synuclein bound to DOPAL (a toxic metabolite of dopamine). However, Serine129-phosphorylated α-synuclein levels were higher in 12-month-old G2019S knock-in mice. Immunohistochemistry confirmed this finding, also showing no genotype difference in 3-month-old mice. We conclude that the G2019S mutation causes progressive dysfunctions of dopamine transporters, along with Serine129-phosphorylated α-synuclein overload, at striatal dopaminergic terminals, which are not associated with dopamine homeostasis dysregulation or neuron loss but might contribute to intrinsic dopaminergic terminal vulnerability. We propose G2019S knock-in mice as a presymptomatic Parkinson’s disease model, useful to investigate the pathogenic interaction among genetics, aging, and internal or environmental factors leading to the disease.

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“…the bar, drag and rotarod tests, were used as described [43, 84, 85]. Experimenters were unaware of genotype and treatments.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Longo

Mercatelli

Novello

et al. 2017

acta neuropathol commun

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“…In contrast to the enhancement of motor function by low doses of NOP receptor antagonist, the inhibitory effects of high concentrations of NOP receptor antagonists were lost in D 2 2/2 mice but not in mice with selective deletion of the long form of the receptor (D 2 L 2/2 ), indicating that the long form is not required for this action. D 2 autoreceptors are thought to be predominantly comprised of the short form of the D 2 receptor (Usiello et al, 2000), and the short form is the predominant D 2 receptor isoform expressed in SNc DA neurons (Jomphe et al, 2006;Viaro et al, 2013). This suggests the specific involvement of D 2 autoreceptors in the inhibitory effects of high doses of NOP receptor antagonists, although again the detailed mechanisms underlying these actions are unclear.…”

Section: B Nociceptin Opioid Peptide Receptor and Motor Functionmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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“…N/OFQ and its receptor are expressed in cortical and subcortical areas of the central nervous system (Neal et al, 2001; Neal et al, 1999a; Neal et al, 1999b), and contribute to the modulation of a number of central functions such as pain, reward, food intake, mood and locomotion (Calo et al, 2000; Lambert, 2008; Mogil and Pasternak, 2001). Mesencephalic dopamine (DA) neurons are involved in motor effects of N/OFQ (Florin et al, 1996; Kuzmin et al, 2004; Viaro et al, 2013). In fact, DA neurons projecting from substantia nigra compacta (SNc) and ventral-tegmental area to the strifatum and prefrontal cortex express the NOP receptor (Maidment et al, 2002; Norton et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of somato-dendritic NOP receptors causes inhibition of the firing activity along the nigro-striatal (Marti et al, 2004b) and meso-accumbal (Murphy and Maidment, 1999) pathways, while activation of presynaptic NOP receptors causes inhibition of DA neurosecretion (Flau et al, 2002). These effects have been associated with hypolocomotion (Murphy, 2010; Narayanan et al, 2004; Sakoori and Murphy, 2004; Viaro et al, 2013). In addition, blockade of NOP receptors in substantia nigra reticulata (SNr) evokes DA release in striatum, suggesting that endogenous N/OFQ exerts a tonically negative control over nigro-striatal DA neurons activity.…”

Section: Introductionmentioning

confidence: 99%

Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease

Arcuri

Viaro

Bido

et al. 2016

Neurobiology of Disease

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To investigate whether the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) contributes to the death of dopamine neurons in Parkinson's disease, we undertook a genetic and a pharmacological approach using NOP receptor knockout (NOP−/−) mice, and the selective and potent small molecule NOP receptor antagonist (−)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Stereological unbiased methods were used to estimate the total number of dopamine neurons in the substantia nigra of i) NOP−/− mice acutely treated with the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), ii) naïve mice subacutely treated with MPTP, alone or in combination with SB-612111, iii) rats injected with a recombinant adeno-associated viral (AAV) vector overexpressing human mutant p.A53T α-synuclein, treated with vehicle or SB-612111. NOP−/− mice showed a 50% greater amount of nigral dopamine neurons spared in response to acute MPTP compared to controls, which was associated with a milder motor impairment. SB-612111, given 4 days after MPTP treatment to mimic the clinical condition, prevented the loss of nigral dopamine neurons and striatal dopaminergic terminals caused by subacute MPTP. SB-612111, administered a week after the AAV injections in a clinically-driven protocol, also increased by 50% both the number of spared nigral dopamine neurons and striatal dopamine terminals, and prevented accompanying motor deficits induced by α-synuclein. We conclude that endogenous N/OFQ contributes to dopamine neuron loss in pathogenic and etiologic models of Parkinson's disease through NOP receptor-mediated mechanisms. NOP receptor antagonists might prove effective as disease-modifying agents in Parkinson's disease, through the rescue of degenerating nigral dopamine neurons and/or the protection of the healthy ones.

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Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands

Cited by 14 publications

References 49 publications

Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease

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