Differential effects of mu- and delta-receptor selective opioid agonists on feedforward and feedback GABAergic inhibition in hippocampal brain slices.

Previous studies have suggested that opioid receptor activation in the hippocampus increases pyramidal neuron excitability by reducing GABAergic inhibition. This hypothesis has received support with regard to mu-receptor agonists but has not been adequately tested with selective delta-receptor agonists. In the present investigation we compared the effects of the selective mu-opioid receptor agonist [Tyr-(D-Ala)-Gly-(N-Me-Phe)-Gly-ol]-enkephalin (DAGO) and the delta-receptor agonist [D-Pen2,D-Pen5]-enkephalin (DPDPE) to those of bicuculline methiodide (BMI) on extracellularly recorded feedforward (FFW) and recurrent (feedback; FB) inhibition. It was discovered that the control population spike response, evoked by Schaffer collateral/commissural axon stimulation, increased in response to DAGO, DPDPE, and BMI, while the secondary or test response increased only in the presence of DAGO and BMI. The resulting hypothesis that delta-opioid receptor activation facilitates synaptically evoked responses independently of a reduction of inhibition was investigated by examining the effect of DPDPE on the field EPSP response recorded in stratum radiatum of CA1, or postsynaptically on a burst response activated through antidromic stimulation of pyramidal neurons in low calcium medium. delta-Opioid receptor activation had no effect on either the field EPSP response or the burst response, suggesting that neither synaptic transmission nor postsynaptic excitability were augmented. Finally, the possibility that DPDPE acts to enhance pyramidal cell excitability independently of GABAergic transmission was further investigated by examining responses to both mu- and delta-opioid agonists following treatment with BMI (30 microM). Responses to DPDPE and DAGO were completely blocked by this treatment, supporting the involvement of a GABAergic circuit in the actions of these enkephalins. These results suggest that the delta-opioid receptor agonist DPDPE may mediate a reduction in GABAergic inhibition which is not detectable using paired stimulation techniques designed to examine FFW and FB inhibition in the hippocampal slice.