L-glutamate and gamma-aminobutyric acid efflux from rat cerebrocortical synaptosomes: modulation by kappa- and mu- but not delta- and opioid receptor like-1 receptors.
The modulation by delta-, kappa-, mu-, and opioid receptor like-1 (ORL(1)) agonists and antagonists of L-glutamate (L-Glu) and gamma-aminobutyric acid (GABA) efflux from superfused rat cerebrocortical synaptosomes was studied. Tetrodotoxin (0.5 microM) inhibited the spontaneous efflux of both transmitters by 20%. Ca(2+) omission decreased GABA and facilitated L-Glu efflux. The neurotransmitter overflow evoked by K(+) concentrations in the 7.5- to 10-mM range was largely Ca(2+) dependent and tetrodotoxin sensitive. Neither the delta-receptor agonist deltorphin (up to 0.3 microM) nor the ORL(1) receptor agonist nociceptin (up to 1 microM) significantly affected either spontaneous or K(+)-evoked neurotransmitter efflux. Conversely, the ORL(1) ligand [Phe(1)(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (0.3 microM) caused a naloxone-sensitive inhibition of both L-Glu- and GABA-stimulated overflow. The kappa-receptor agonist (-)-U50,488 failed to modulate spontaneous L-Glu and GABA efflux. However, it similarly inhibited the K(+)-evoked overflow of both neurotransmitters (EC(50) approximately 100 nM; E(max) approximately 25-30% inhibition) in a norbinaltorphimine-sensitive manner. The selective mu-receptor agonist endomorphin 1 inhibited both spontaneous (EC(50) approximately 50 nM) and K(+)-evoked (EC(50) approximately 10 nM; E(max) approximately 50% inhibition) L-Glu efflux in a naloxone-sensitive manner. Conversely, it significantly inhibited only K(+)-evoked GABA efflux (EC(50) approximately 10 nM), although with a lower maximal effect (E(max) approximately 25-30% inhibition). It is concluded that, in the rat cerebral cortex, L-Glu and GABA efflux from nerve terminals is under the direct inhibitory control of kappa- and mu- (but not delta- or ORL(1)) receptors. Because glutamatergic terminals emerged as a preferential target of mu-receptor agonists, the activation of this receptor may advocate both relevant analgesic and neuroprotective effects.
Sbrenna
S
S
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy. mri@ifeuniv.unife.it
Marti
M
M
Morari
M
M
Calo
G
G
Guerrini
R
R
Beani
L
L
Bianchi
C
C
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013268:Stimulation, Chemical; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000094942:Nociceptin Receptor
D018698:Glutamic Acid; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011188:Potassium; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D000094942:Nociceptin Receptor; C000722285:Oprl1 protein, rat