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

1. 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. 2. 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 microM and naloxone benzoylhydrazone 5 microM 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 microM in guinea-pig retinal discs. Ac-RYYRIK-NH(2) 0.032 microM did not affect the evoked overflow by itself whereas naloxone benzoylhydrazone 5 microM inhibited it in each tissue. 3. 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 microM. Ac-RYYRIK-NH(2) and naloxone benzoylhydrazone showed apparent pA(2) values of 8.6 and 6.9. 4. 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.