Abstract

The modulation by δ-, κ-, μ-, and opioid receptor like-1 (ORL₁) agonists and antagonists ofl-glutamate (l-Glu) and γ-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 δ-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 bothl-Glu- and GABA-stimulated overflow. The κ-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 κ- and μ- (but not δ- 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.