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

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. [Copyright &y& Elsevier]