δ and μ Enkephalins Inhibit Spontaneous GABA-mediated IPSCs via a Cyclic AMP-Independent Mechanism in the Rat Hippocampus

Abstract

The effects of enkephalins selective for δ and μ opioid receptors on inhibitory postsynaptic currents (IPSCs) mediated by GABA were studied in chloride-loaded CA1 pyramidal neurons in adult rat hippocampal slices. The μ agonist DAMGO (0.1 μM) significantly reduced the amplitudes of evoked monosynaptic IPSCs, recorded following the antagonism of excitatory glutamate receptors, and this effect was reversed by the μ antagonist CTOP (1 μM). The selective δ receptor agonists DPDPE and D-Ala2-deltorphin II (both 0.1-0.5 μM) had no effect on these evoked currents. In contrast, the frequency of tetrodotoxin-resistant spontaneous miniature GABA-mediated currents (m-IPSCs) was significantly reduced by both DPDPE (0.1-0.5 μM) and DAMGO (0.1-0.5 μM), while the amplitudes of these events were unaltered. These effects were reversed by the selective δ antagonist ICI 174,864 (1 μM) and the selective μ antagonist CTOP (1 μM), respectively. To investigate the mechanisms of this μ and δ receptor-mediated modulation of GABA release, and the possible involvement of a cAMP-sensitive K+ conductance, spontaneous action potential-dependent IPSCs (s-IPSCs) were measured following pretreatment with 8-bromo-cAMP (8-Br-cAMP). 8-Br-cAMP (250 μM) had no effect alone on the amplitude or frequency of s-IPSCs, nor did it after the inhibitory effects of the δ and μ agonists. These results indicate that δ and μ opioid receptor activation inhibits spontaneous GABA release, independently of cAMP, through direct actions at inhibitory nerve terminals, and that δ opioids inhibit spontaneous but not evoked GABA release in the hippocampus.