Inhibition of glutamate release by presynaptic kappa 1-opioid receptors in the guinea pig dentate gyrus.

1. Activation of kappa 1-opioid receptors inhibits excitatory transmission in the hippocampal dentate gyrus of the guinea pig. The present studies used both anatomic and physiological approaches to distinguish between a pre- and postsynaptic localization of these receptors. 2. The entorhinal cortex was lesioned unilaterally to cause degeneration of perforant path afferents to the dentate molecular layer, and kappa 1-opioid binding sites were measured by labeling with the selective agonist, [3H]-U69593. Binding density was reduced significantly in the dentate gyrus molecular layer ipsilateral to the lesion compared with the contralateral molecular layer and with sham-lesioned controls. 3. Paired-pulse facilitation is a neurophysiologic paradigm that has been used to differentiate pre- and postsynaptic sites of action for agents that inhibit excitatory neurotransmission. U69593 reduced the amplitude of single population spikes and increased the degree of paired pulse facilitation. The potentiation of paired-pulse facilitation was maintained when the stimulation intensity was increased to compensate for the inhibition of excitatory transmission. These effects of kappa 1-receptor activation were similar to those seen after presynaptic inhibition of excitatory neurotransmitter release and support the hypothesis that U69593 presynaptically inhibits excitatory amino acid release in the dentate gyrus. 4. Local application of glutamate by pressure ejection in the dentate molecular layer evoked field excitatory postsynaptic potentials that mimicked those evoked by electrical stimulation of the perforant path. Both responses were sensitive to the non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione. U69593 inhibited responses evoked by perforant path stimulation but had no effect on responses evoked by glutamate application.(ABSTRACT TRUNCATED AT 250 WORDS)