Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior

Matteo Marti, Flora Mela, Carlo Veronesi, Remo Guerrini, Severo Salvadori, Mauro Federici, Nicola B. Mercuri, Anna Rizzi, Gianfranco Franchi, Lorenzo Beani, Clementina Bianchi, Michele Morari

Research output: Contribution to journalArticle

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Abstract

A multidisciplinary approach was followed to investigate whether the opioid-like peptide nociceptin/orphanin FQ (N/OFQ) regulates the nigrostriatal dopaminergic pathway and motor behavior. Nigrostriatal dopaminergic cells, which express N/OFQ peptide (NOP) receptors, are located in the substantia nigra pars compacta and extend their dendrites in the substantia nigra pars reticulata, thereby modulating the basal ganglia output neurons. In vitro electrophysiological recordings demonstrated that N/OFQ hyperpolarized the dopaminergic cells of the substantia nigra pars compacta and inhibited their firing activity. In vivo dual-probe microdialysis showed that N/OFQ perfused in the substantia nigra pars reticulata reduced dopamine release in the ipsilateral striaturn, whereas UFP-101 ([Nphe 1, Arg 14, Lys 15]N/OFQ(1-13)-NH2) (a selective NOP receptor peptide antagonist) stimulated it. N/OFQ microinjected in the substantia nigra pars reticulata impaired rat performance on a rotarod apparatus, whereas UFP-101 enhanced it. Electromyography revealed that N/OFQ and UFP-101 oppositely affected muscle tone, inducing relaxation and contraction of triceps, respectively. The selective NOP receptor nonpeptide antagonist J-113397 (1-[3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H benzimidazol-2-one), either injected intranigrally or given systemically, also elevated striatal dopamine release and facilitated motor activity, confirming that these effects were caused by blockade of endogenous N/OFQ signaling. The inhibitory role played by endogenous N/OFQ on motor activity was additionally strengthened by the finding that mice lacking the NOP receptor gene outperformed wild-type mice on the rotarod. We conclude that NOP receptors in the substantia nigra pars reticulata, activated by endogenous N/OFQ, drive a physiologically inhibitory control on motor behavior, possibly via modulation of the nigrostriatal dopaminergic pathway.

Original languageEnglish
Pages (from-to)6659-6666
Number of pages8
JournalJournal of Neuroscience
Volume24
Issue number30
DOIs
Publication statusPublished - Jul 28 2004

Fingerprint

Peptide Receptors
Pars Reticulata
nociceptin receptor
nociceptin
Dopamine
Motor Activity
Efferent Pathways
Corpus Striatum
Opioid Peptides
Microdialysis
Electromyography
Dendrites
Basal Ganglia
Neurons
Muscles
Peptides
Genes
(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)

Keywords

  • Dopamine release
  • J-113397
  • Microdialysis
  • Motor activity
  • N/OFQ
  • Nociceptin/orphanin FQ
  • Substantia nigra
  • UFP-101

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior. / Marti, Matteo; Mela, Flora; Veronesi, Carlo; Guerrini, Remo; Salvadori, Severo; Federici, Mauro; Mercuri, Nicola B.; Rizzi, Anna; Franchi, Gianfranco; Beani, Lorenzo; Bianchi, Clementina; Morari, Michele.

In: Journal of Neuroscience, Vol. 24, No. 30, 28.07.2004, p. 6659-6666.

Research output: Contribution to journalArticle

Marti, Matteo ; Mela, Flora ; Veronesi, Carlo ; Guerrini, Remo ; Salvadori, Severo ; Federici, Mauro ; Mercuri, Nicola B. ; Rizzi, Anna ; Franchi, Gianfranco ; Beani, Lorenzo ; Bianchi, Clementina ; Morari, Michele. / Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 30. pp. 6659-6666.
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AU - Mercuri, Nicola B.

AU - Rizzi, Anna

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