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Titolo/Abstract/Parole chiave

Nociceptin/orphanin FQ and motor activity: behavioural, biochemical and electrophysiological studies in models of Parkinson’s disease

Viaro, Riccardo (2010) Nociceptin/orphanin FQ and motor activity: behavioural, biochemical and electrophysiological studies in models of Parkinson’s disease. Tesi di Dottorato , Università degli Studi di Ferrara.

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    Abstract

    Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide which activates the NOP receptor. N/OFQ exerts an inhibitory control on locomotion through inhibition of dopamine (DA) neurons located in the substantia nigra (SN), which degenerate in Parkinson’s disease (PD). In the present study, we demonstrated that NOP receptor antagonists facilitated and inhibited motor behavior in 1-methyl-4-phenyl-1,2,5,6- tetrahydropyridine (MPTP)-treated mice and nonhuman primates depending on dose. In naïve mice, we found that dual response to NOP receptor antagonists was DAdependent and mediated by D2 postsynaptic (facilitation) and D2 presynaptic receptors (inhibition). Consistently, inhibition induced by high doses of NOP receptor antagonists in MPTP-treated mice was reversed by D2 receptor blockade, leading to a widening of their therapeutic window. Evidence that endogenous N/OFQ not only sustains symptoms but also contributes to neurodegeneration in PD was also provided. In fact, NOP receptor knockout mice were found to be partially resistant against MPTP-induced loss of nigral DA cells. In order to understand the mechanisms underlying motor effects of endogenous N/OFQ, we investigated the role of nigral NOP receptors in the control of motor cortex (M1) output. Motor inhibition induced by exogenous N/OFQ was associated with reduction in M1 excitability while the opposite was true for motor facilitation induced by NOP receptor antagonists. Finally, we investigated M1 reorganization in parkinsonian conditions and found that M1 excitability was decreased after 6-OHDA lesioning in rats. We concluded that endogenous N/OFQ controls motor activity via NOP receptors located in SN and through modulation of DA transmission, leading to changes in activity of the basal ganglia-thalamo-cortical pathway and M1 output. Moreover, we provide evidence that NOP receptor antagonists may represent a novel approach for symptomatic and neuroprotective therapy of PD.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:19 Marzo 2010
    Relatore:Morari, Michele
    Coordinatore ciclo:Borea, Andrea
    Istituzione:Università degli Studi di Ferrara
    Dottorato:XXII Anno 2007 > FARMACOLOGIA E ONCOLOGIA MOLECOLARE
    Struttura:Dipartimento > Medicina clinica e sperimentale
    Soggetti:Area 05 - Scienze biologiche > BIO/14 Farmacologia
    Parole chiave:motor activity, motor cortex, neuroprotection, nociceptin, NOP receptor antagonists, Parkinson's disease
    Depositato il:23 Lug 2010 07:49

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