DUAL INHIBITORY-ACTION OF ENADOLINE (CI977) ON RELEASE OF AMINO-ACIDS IN THE RAT HIPPOCAMPUS

The effect of the kappa-opioid receptor agonist enadoline (CI977, (5R)-(5 alpha,7 alpha,8 beta)-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 mu M, 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 kappa-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 gamma-aminobutyric acid (GABA) was reduced by 250 mu M CI977 in the probe. The effect of CI977 on release of glutamate and aspartate, but not of GABA, was reversed by nor-binaltorphimine (45 mu M). 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 mu M and release of GABA by 250 mu M CI977 in the probe, and this effect was not modified by nor-binaltorphimine (58 mu M). 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 K-opioid receptor; the more potent inhibition appears to be connected with Na+ channels.