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

Br J Pharmacol. 2000 May;130(2):425-33. doi: 10.1038/sj.bjp.0703321.


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 microM tetrodotoxin or Ca(2+)-omission. Ten mM 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 microM. 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 nM, respectively; E(max)=28 and 29% inhibition, respectively) in a norBinaltorphimine- (0.3 microM) and naloxone- (1 microM) 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 nM) and K(+)-evoked (EC(50)=13 nM; E(max)=52% inhibition) [(3)H]-5-HT efflux. The effect of NC was insensitive to naloxone (up to 10 microM), 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)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) also inhibited K(+) stimulated [(3)H]-5-HT overflow (EC(50)=64 nM; E(max)=31% inhibition), but its effect was partially antagonized by 10 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Biological Transport
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Drug Interactions
  • In Vitro Techniques
  • Male
  • Narcotics / pharmacology*
  • Neurotransmitter Agents / metabolism
  • Oligopeptides / pharmacology
  • Opioid Peptides / pharmacology*
  • Peptide Fragments / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism
  • Serotonin / metabolism*
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism
  • Vasodilator Agents / pharmacology


  • Analgesics, Opioid
  • Narcotics
  • Neurotransmitter Agents
  • Oligopeptides
  • Opioid Peptides
  • Peptide Fragments
  • Receptors, Opioid
  • Vasodilator Agents
  • endomorphin 1
  • nociceptin (1-13)-NH2, Phe(1)-psi(CH2-NH)-Gly(2)-
  • Serotonin
  • nociceptin
  • nociceptin receptor