Elsevier

Neuroscience

Volume 112, Issue 1, 12 June 2002, Pages 153-160
Neuroscience

Nociceptin/orphanin FQ receptors modulate glutamate extracellular levels in the substantia nigra pars reticulata. A microdialysis study in the awake freely moving rat

https://doi.org/10.1016/S0306-4522(02)00050-7Get rights and content

Abstract

Intracerebral microdialysis was employed in awake freely moving rats to investigate the effects of nociceptin/orphanin FQ receptor ligands on glutamate extracellular levels in the substantia nigra pars reticulata. Nociceptin/orphanin FQ, ineffective at 0.1 μM, induced a prolonged stimulation of nigral glutamate levels at 1 and 10 μM (mean effect of 137±9 and 167±13%, respectively, of basal values). These effects were prevented by the novel nociceptin/orphanin FQ receptor antagonist [Nphe1]nociceptin/orphanin FQ(1-13)NH2 (100 and 300 μM, respectively) but not by the non-selective opioid receptor antagonist naloxone (10 μM). [Nphe1]nociceptin/orphanin FQ(1-13)NH2 (100 μM) inhibited by itself glutamate outflow (maximal reduction to 71±4%) while naloxone was ineffective. The nociceptin/orphanin FQ receptor ligand [Phe1ψ(CH2-NH)Gly2]nociceptin/orphanin FQ(1-13)NH2 also facilitated glutamate outflow at 10 μM (mean effect of 145±10%). Intranigral perfusion with tetrodotoxin (1 μM) or with the dopamine D2 receptor antagonist raclopride (1 μM), failed to affect basal glutamate output and prevented the facilitatory effect of nociceptin/orphanin FQ (10 μM). However, perfusion with the GABAA receptor antagonist bicuculline (10 μM) increased local glutamate extracellular levels by itself and attenuated the effect of the peptide.

Our data suggest that nociceptin/orphanin FQ increases glutamate extracellular levels in the substantia nigra pars reticulata via activation of nociceptin/orphanin FQ receptors located on non-glutamatergic, possibly dopaminergic and GABAergic, neuronal elements.

Section snippets

Experimental procedures

Male Sprague–Dawley rats (300–350 g weight; Stefano Morini, Reggio Emilia, Italy) were kept under regular lighting conditions (12 h light/dark cycle) and given food and water ad libitum. Experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and adequate measures were taken to minimize animal pain or discomfort. The experimental protocols performed in the present study were also approved by the Italian Ministero della Sanità

Results

Basal GLU extracellular levels in the SNr were stable over the time course of the experiment (Fig. 1). Spontaneous GLU output was unaffected by local perfusion with submicromolar (0.1 μM) N/OFQ concentrations but was increased by perfusion with N/OFQ 1 and 10 μM (H=19.77, n=48, P=0.0002; Fig. 1). Basal GLU extracellular levels rose slowly during perfusion with N/OFQ 1 μM (peak effect of 148±9%, 30 min after onset of perfusion) while responding promptly to N/OFQ 10 μM (150±14%, 10 min after

Discussion

A major finding of the present microdialysis study was that perfusion with N/OFQ in the SNr evoked an increase of local GLU extracellular levels which was insensitive to naloxone but prevented by the novel N/OFQ receptor antagonist [Nphe1]N/OFQ(1-13)NH2. The stimulation brought about by N/OFQ was also prevented by the D2 receptor antagonist raclopride and partially antagonized by the GABAA receptor antagonist bicuculline.

The pharmacological approach to the N/OFQ–N/OFQ receptor system has been

Conclusion

The microdialysis technique in awake freely moving rats has allowed the demonstration of a phasic facilitatory regulation of nigral GLU outflow mediated by local perfusion with N/OFQ in the SNr. Naloxone-insensitive and [Nphe1]-sensitive N/OFQ receptors, possibly located on dopaminergic, and perhaps GABAergic, neuronal structures, may be involved. The possibility that the inhibitory effect of [Nphe1] on spontaneous GLU outflow reflects the existence of a N/OFQergic facilitatory tone requires

Acknowledgments

This work has been supported by grants from the Consiglio Nazionale delle Ricerche (No. 9704432CT04) and from the Italian Ministry of the University (co-fin 99).

References (61)

  • J.C. Meunier

    Nociceptin/orphanin FQ and the opioid receptor-like ORL1 receptor

    Eur. J. Pharmacol.

    (1997)
  • M. Morari et al.

    Reciprocal dopamine-glutamate modulation of release in the basal ganglia

    Neurochem. Int.

    (1998)
  • M. Morari et al.

    Functional neuroanatomy of the nigrostriatal and the striatonigral pathways as studied with dual probe microdialysis in the awake rat. I. Effects of perfusion with tetrodotoxin and low-calcium medium

    Neuroscience

    (1996)
  • M. Morelli et al.

    Substantia nigra as a site of origin of dopamine dependent motor syndromes induced by stimulation of μ and δ opioid receptors

    Brain Res.

    (1989)
  • N.P. Murphy et al.

    Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats

    Neuroscience

    (1996)
  • H. Okawa et al.

    Effect of nociceptinNH2 and [Nphe1]nociceptin(1-13)NH2 on rat brain noradrenaline release in vivo and in vitro

    Neurosci. Lett.

    (2001)
  • R.K. Reinscheid et al.

    Structures that delineate orphanin FQ and dynorphin A pharmacological selectivities

    J. Biol. Chem.

    (1998)
  • E. Rinvik et al.

    Terminals of subthalamonigral fibres are enriched with glutamate-like immunoreactivity: an electron microscopy, immunogold analysis in the cat

    J. Chem. Neuroanat.

    (1993)
  • P. Robledo et al.

    Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiologicol data

    Brain Res.

    (1990)
  • E. Schlicker et al.

    Nociceptin and neurotransmitter release in CNS

    Peptides

    (2000)
  • H. Tokuno et al.

    A morphological evidence for monosynaptic projection from the nucleus peduncolopontinus pars compacta (TPC) to nigrostriatal projection neurons

    Neurosci. Lett.

    (1988)
  • L. Turski et al.

    The role of the substantia nigra in motility of the rat. Muscular rigidity, body asymmetry and catalepsy after injection of morphine into the nigra

    Neuropharmacology

    (1983)
  • J. Abarca et al.

    Changes in extracellular levels of glutamate and aspartate in the rat substantia nigra induced by dopamine receptor ligands: in vivo microdialysis study

    Neurochem. Res.

    (1995)
  • D. Albrecht et al.

    Inhibitory action of nociceptin/orphanin FQ on functionally different thalamic neurons in urethane-anaesthetized rats

    Br. J. Pharmacol.

    (2001)
  • B. Anton et al.

    Immunohistochemical localization of ORL-1 in the central nervous system of the rat

    J. Comp. Neurol.

    (1996)
  • H. Berger et al.

    [Nphe(1)]NC(1-13)NH(2) selectively antagonizes nociceptin/orphanin FQ-stimulated G-protein activation in rat brain

    J. Pharmacol. Exp. Ther.

    (2000)
  • B. Buzas et al.

    Regulation of nociceptin/orphanin FQ gene expression by neuropoietic cytokines and neurotrophic factors in neurons and astrocytes

    J. Neurochem.

    (1999)
  • G. Calò et al.

    Structure–activity study of the nociceptin(1-13)-NH2 N-terminal tetrapeptide and discovery of a nociceptin receptor antagonist

    J. Med. Chem.

    (1998)
  • G. Calò et al.

    Pharmacology of nociceptin and its receptor: a novel therapeutic target

    Br. J. Pharmacol.

    (2000)
  • G. Calò et al.

    Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay

    Br. J. Pharmacol.

    (1998)
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