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The novel nociceptin/orphanin FQ receptor antagonist Trap‐101 alleviates experimental parkinsonism through inhibition of the nigro‐thalamic pathway: positive interaction with L ‐DOPA
Author(s) -
Marti Matteo,
Trapella Claudio,
Morari Michele
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05735.x
Subject(s) - nociceptin receptor , nop , chemistry , receptor antagonist , substantia nigra , pharmacology , parkinsonism , medicine , opioid receptor , endocrinology , microdialysis , antagonist , receptor , opioid , dopamine , opioid peptide , biochemistry , dopaminergic , disease
In this study we investigated whether the recently discovered antagonist of the nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor, 1‐[1‐(cyclooctylmethyl)‐1,2,3,6‐tetrahydro‐5‐(hydroxymethyl)‐4‐pyridinyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one (Trap‐101) changed motor activity in naïve rats and mice, and alleviated parkinsonism in 6‐hydroxydopamine hemilesioned rats. In naïve rats, Trap‐101 stimulated motor activity at 10 mg/Kg and inhibited it at 30 mg/Kg. Such dual action was also observed in wild‐type but not NOP receptor knockout mice suggesting specific involvement of NOP receptors. Trap‐101 alleviated akinesia/bradykinesia and improved overall gait ability in hemiparkinsonian rats, being effective starting at 1 mg/Kg and without worsening motor deficit at 30 mg/Kg. To investigate the circuitry involved in the Trap‐101 action, behavioral tests were performed in rats undergoing microdialysis. The anti‐akinetic/anti‐bradykinetic effects of Trap‐101, given systemically (10 mg/Kg) or perfused in substantia nigra reticulata (10 μM), were associated with reduced glutamate and enhanced GABA release in substantia nigra, and reduced GABA release in ipsilateral ventro‐medial thalamus. When combined with ineffective doses of l ‐DOPA (0.1 mg/Kg), Trap‐101 evoked larger neurochemical and behavioral responses. These data show that Trap‐101 is an effective NOP receptor antagonist in vivo and confirm that NOP receptor antagonists alleviate parkinsonism through blockade of nigral NOP receptors and impairment of nigro‐thalamic transmission.