Vol. 291, Issue 3, 1365-1371, December 1999

L-Glutamate and -Aminobutyric Acid Efflux from Rat Cerebrocortical Synaptosomes: Modulation by - and µ- but Not - and Opioid Receptor Like-1 Receptors¹

Simone Sbrenna, Matteo Marti, Michele Morari, Girolamo Calo, Remo Guerrini, Lorenzo Beani and Clementina Bianchi

Department of Experimental and Clinical Medicine, Section of Pharmacology (S.S., M.Ma., M. Mo., G.C., L.B., C.B.), and Department of Pharmaceutical Sciences (R.G.), University of Ferrara, Ferrara, Italy

The modulation by -, -, µ-, and opioid receptor like-1 (ORL₁) agonists and antagonists of L-glutamate (L-Glu) and -aminobutyric acid (GABA) efflux from superfused rat cerebrocortical synaptosomes was studied. Tetrodotoxin (0.5 µM) inhibited the spontaneous efflux of both transmitters by 20%. Ca²⁺ 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 Ca²⁺ dependent and tetrodotoxin sensitive. Neither the -receptor agonist deltorphin (up to 0.3 µM) nor the ORL₁ receptor agonist nociceptin (up to 1 µM) significantly affected either spontaneous or K⁺-evoked neurotransmitter efflux. Conversely, the ORL₁ ligand [Phe¹(CH₂-NH)Gly²]nociceptin(1-13)NH₂ (0.3 µM) caused a naloxone-sensitive inhibition of both L-Glu- and GABA-stimulated overflow. The -receptor agonist ()-U50,488 failed to modulate spontaneous L-Glu and GABA efflux. However, it similarly inhibited the K⁺-evoked overflow of both neurotransmitters (EC₅₀ ~100 nM; E_max ~25-30% inhibition) in a norbinaltorphimine-sensitive manner. The selective µ-receptor agonist endomorphin 1 inhibited both spontaneous (EC₅₀ ~50 nM) and K⁺-evoked (EC₅₀ ~10 nM; E_max ~50% inhibition) L-Glu efflux in a naloxone-sensitive manner. Conversely, it significantly inhibited only K⁺-evoked GABA efflux (EC₅₀ ~10 nM), although with a lower maximal effect (E_max ~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 - and µ- (but not - or ORL₁) receptors. Because glutamatergic terminals emerged as a preferential target of µ-receptor agonists, the activation of this receptor may advocate both relevant analgesic and neuroprotective effects.