DELTA-ENKEPHALIN AND MU-ENKEPHALIN INHIBIT SPONTANEOUS GABA-MEDIATED IPSCS VIA A CYCLIC-AMP-INDEPENDENT MECHANISM IN THE RAT HIPPOCAMPUS

The effects of enkephalins selective for delta and mu opioid receptors on inhibitory postsynaptic currents (IPSCs) mediated by GABA were stu died in chloride-loaded CA1 pyramidal neurons in adult rat hippocampal slices. The mu agonist DAMGO (0.1 mu M) significantly reduced the amp litudes of evoked monosynaptic IPSCs, recorded following the antagonis m of excitatory glutamate receptors, and this effect was reversed by t he mu antagonist CTOP (1 mu M). The selective delta receptor agonists DPDPE and D-Ala(2)-deltorphin II (both 0.1-0.5 mu M) had no effect on these evoked currents. In contrast, the frequency of tetrodotoxin-resi stant spontaneous miniature GABA-mediated currents (m-IPSCs) was signi ficantly reduced by both DPDPE (0.1-0.5 mu M) and DAMGO (0.1-0.5 mu M) , while the amplitudes of these events were unaltered. These effects w ere reversed by the selective delta antagonist ICI 174,864 (1 mu M) an d the selective mu antagonist CTOP (I mu M), respectively. To investig ate the mechanisms of this mu and delta receptor-mediated modulation o f GABA release, and the possible involvement of a cAMP-sensitive K+ co nductance, spontaneous action potential-dependent IPSCs (s-IPSCs) were measured following pretreatment with 8-bromo-cAMP (8-Br-cAMP). 8-Br-c AMP (250 mu M) had no effect alone on the amplitude or frequency of s- IPSCs, nor did it alter the inhibitory effects of the delta and mu ago nists. These results indicate that delta and mu opioid receptor activa tion inhibits spontaneous GABA release, independently of cAMP, through direct actions at inhibitory nerve terminals, and that delta opioids inhibit spontaneous but not evoked GABA release in the hippocampus.