Dual inhibitory action of enadoline (CI977) on release of amino acids in the rat hippocampus

Abstract The effect of the κ-opioid receptor agonist enadoline (CI977, (5 R )-(5α,7α,8β)- N -methyl- N -[7-(1-pyrrilidinyl)-1-oxaspiro[4,5]dec-8-yl-4-benzofuranacetamide monohydrochloride), on the release of amino acids was studied in the hippocampus of freely moving rats. K + , 100 mM, or veratrine, 100 μM, were applied for 10 min via the dialysis probe, either alone (control groups) or together with CI977 (after a 10 min pretreatment with CI977 in the perfusion medium). To test the specificity of the response to CI977, nor-binaltorphimine, a selective κ-opioid receptor antagonist, was delivered together with CI977 in two groups of animals. To test the effect of systemic injection, CI977 was given subcutaneously 30 min prior to either stimulus. K + -induced release of glutamate and aspartate was significantly reduced by CI977, 2.5 mM; release of γ-aminobutyric acid (GABA) was reduced by 250 μM CI977 in the probe. The effect of CI977 on release of glutamate and aspartate, but not of GABA, was reversed by nor-binaltorphimine (45 μM). Systemic treatment with CI977, 1 or 10 mg/kg, did not reduce K + -induced release of glutamate. Veratrine-induced release of aspartate and glutamate was significantly inhibited by 25 μM and release of GABA by 250 μM CI977 in the probe, and this effect was not modified by nor-binaltorphimine (58 μM). Systemic injection of CI977 1 mg/kg significantly reduced veratrine-induced release of glutamate. These results indicate that CI977 regulates release of amino acids by two independent mechanisms. The weaker inhibition of the stimulated release involved activation of the κ-opioid receptor; the more potent inhibition appears to be connected with Na + channels.