Inhibition of striatal and retinal dopamine release via nociceptin/orphanin FQ receptors

We determined the effects of nociceptin/orphanin FQ and the NOP receptor ligands acetyl‐Arg‐Tyr‐Tyr‐Arg‐Ile‐Lys‐NH 2 (Ac‐RYYRIK‐NH 2 ) and naloxone benzoylhydrazone on transmitter release in vitro . The electrically evoked tritium overflow from guinea‐pig and mouse striatal slices and guinea‐pig retinal discs preincubated with [ 3 H]‐dopamine was inhibited by nociceptin/orphanin FQ (pEC 50 7.9, 7.6 and 8.6; E max 30, 50 and 55%). Ac‐RYYRIK‐NH 2 0.032 μ M and naloxone benzoylhydrazone 5 μ M antagonized the effect of nociceptin/orphanin FQ in striatal slices of the guinea‐pig (apparent pA 2 9.1 and 6.8) and the mouse (apparent pA 2 9.2 and 7.5) and strongly attenuated the effect of nociceptin/orphanin FQ 0.1 μ M in guinea‐pig retinal discs. Ac‐RYYRIK‐NH 2 0.032 μ M did not affect the evoked overflow by itself whereas naloxone benzoylhydrazone 5 μ M inhibited it in each tissue. The electrically evoked tritium overflow from mouse brain cortex slices preincubated with [ 3 H]‐noradrenaline was inhibited by nociceptin/orphanin FQ (pEC 50 7.9, E max 85%), Ac‐RYYRIK‐NH 2 (pEC 50 8.3, E max 47%) but not affected by naloxone benzoylhydrazone 5 μ M . Ac‐RYYRIK‐NH 2 and naloxone benzoylhydrazone showed apparent pA 2 values of 8.6 and 6.9. In conclusion, the inhibitory effect of nociceptin/orphanin FQ on dopamine release in the striatum and retina and on noradrenaline release in the cerebral cortex is mediated via NOP receptors. Ac‐RYYRIK‐NH 2 behaves as an extremely potent NOP receptor antagonist in the striatum and retina and as a partial agonist in the cortex.British Journal of Pharmacology (2002) 137 , 1355–1361. doi: 10.1038/sj.bjp.0704998