L-glutamate and gamma-aminobutyric acid efflux from rat cerebrocortical synaptosomes: Modulation by kappa- and mu- but not delta- and opioid receptorlike-1 receptors

The modulation by delta-, kappa-, mu-, and opioid receptor like-1 (ORL1) ag onists and antagonists of L-glutamate (L-Glu) and gamma-aminobutyric acid ( GABA) efflux from superfused rat cerebrocortical synaptosomes was studied. Tetrodotoxin (0.5 mu M) inhibited the spontaneous efflux of both transmitte rs by 20%. Ca2+ omission decreased GABA and facilitated L-Glu efflux. The n eurotransmitter overflow evoked by K+ concentrations in the 7.5- to 10-mM r ange was largely Ca2+ dependent and tetrodotoxin sensitive. Neither the del ta-receptor agonist deltorphin (up to 0.3 mu M) nor the ORL1 receptor agoni st nociceptin (up to 1 mu M) significantly affected either spontaneous or K +-evoked neurotransmitter efflux. Conversely, the ORL1 ligand [Phe(1)(CH2-N H)Gly(2)]nociceptin(1-13)NH2 (0.3 mu M) caused a naloxone-sensitive inhibit ion 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 (E C50 similar to 100 nM; E-max similar to 25-30% inhibition) in a norbinaltor phimine- sensitive manner. The selective mu-receptor agonist endomorphin 1 inhibited both spontaneous (EC50 similar to 50 nM) and K+-evoked (EC50 simi lar to 10 nM; E-max similar to 50% inhibition) L-Glu efflux in a naloxone-s ensitive manner. Conversely, it significantly inhibited only K+-evoked GABA efflux (EC50 similar to 10 nM), although with a lower maximal effect (E-ma x similar to 25-30% inhibition). It is concluded that, in the rat cerebral cortex, L-Glu and GABA efflux from nerve terminals is under the direct inhi bitory control of kappa- and mu- (but not delta- or ORL1) receptors. Becaus e glutamatergic terminals emerged as a preferential target of mu-receptor a gonists, the activation of this receptor may advocate both relevant analges ic and neuroprotective effects.