Modulation of 5‐hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin

The modulation of [ 3 H]‐5‐hydroxytryptamine ([ 3 H]‐5‐HT) efflux from superfused rat cortical synaptosomes by delta, kappa, mu and ORL 1 opioid receptor agonists and antagonists was studied. Spontaneous [ 3 H]‐5‐HT efflux was reduced (20% inhibition) by either 0.5 μ M tetrodotoxin or Ca 2+ ‐omission. Ten m M K + ‐evoked [ 3 H]‐5‐HT overflow was largely Ca 2+ ‐dependent (90%) and tetrodotoxin‐sensitive (50%). The delta receptor agonist, deltorphin‐I, failed to modulate the K + ‐evoked neurotransmitter efflux up to 0.3 μ M . The kappa and the mu receptor agonists, U‐50,488 and endomorphin‐1, inhibited K + ‐evoked [ 3 H]‐5‐HT overflow (EC 50 =112 and 7 n M , respectively; E max =28 and 29% inhibition, respectively) in a norBinaltorphimine‐ (0.3 μ M ) and naloxone‐ (1 μ M ) sensitive manner, respectively. None of these agonists significantly affected spontaneous [ 3 H]‐5‐HT efflux. The ORL 1 receptor agonist nociceptin inhibited both spontaneous (EC 50 =67 n M ) and K + ‐evoked (EC 50 =13 n M ; E max =52% inhibition) [ 3 H]‐5‐HT efflux. The effect of NC was insensitive to naloxone (up to 10 μ M ), but was antagonized by [Nphe 1 ]nociceptin(1‐13)NH 2 (a novel selective ORL 1 receptor antagonist; pA 2 =6.7) and by naloxone benzoylhydrazone (pA 2 =6.3). The ORL 1 ligand [Phe 1 ψ(CH 2 ‐NH)Gly 2 ]nociceptin(1‐13)NH 2 also inhibited K + stimulated [ 3 H]‐5‐HT overflow (EC 50 =64 n M ; E max =31% inhibition), but its effect was partially antagonized by 10 μ M naloxone. It is concluded that the ORL 1 receptor is the most important presynaptic modulator of neocortical 5‐HT release within the opioid receptor family. This suggests that the ORL 1 /nociceptin system may have a powerful role in the control of cerebral 5‐HT‐mediated biological functions.British Journal of Pharmacology (2000) 130 , 425–433; doi: 10.1038/sj.bjp.0703321