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 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.
Sbrenna
S
S
Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17-19, University of Ferrara, 44100 Ferrara, Italy.
Marti
M
M
Morari
M
M
Calo'
G
G
Guerrini
R
R
Beani
L
L
Bianchi
C
C
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D066298:In Vitro Techniques; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000701:Analgesics, Opioid; D009294:Narcotics; D018377:Neurotransmitter Agents; D009842:Oligopeptides; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D012701:Serotonin; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C105293:endomorphin 1; C114149:nociceptin (1-13)-NH2, Phe(1)-psi(CH2-NH)-Gly(2)-; C000722285:Oprl1 protein, rat