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

Abstract

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.

Complementary Modulation of Somatic Inhibition by Opioids and Cannabinoids

“…Whereas opioids strongly increase hippocampal excitability and can induce epileptic activity (Lee et al, 1989;Lupica and Dunwiddie, 1991), cannabinoids subtly disrupt the timing without changing the overall rate of activity (Paton et al, 1998;Robbe et al, 2006). This suggests that opioids and cannabinoids affect inhibitory systems in a different manner.…”

“…The selective modulation of feedback inhibition by cannabinoids will increase the tendency of pyramidal cells to burst (Robbe et al, 2006) and disrupt oscillatory activity (Hajos et al, 2000). In contrast, because opioids selectively modulate feedforward inhibition, they will increase the spiking probability in response to afferent excitation, increase the integration time window, and decrease the synchrony of hippocampal pyramidal cells (Lupica and Dunwiddie, 1991;Pouille and Scanziani, 2001). Given that opioids increase the excitability of pyramidal cells, we were surprised that the amplitude of feedback inhibition did not increase in the presence of DAMGO.…”

“…Their effects on hippocampal activity are, however, qualitatively different: whereas -opioids strongly increase the spiking probability of pyramidal cells (Lupica and Dunwiddie, 1991), cannabinoids more subtly alter their temporal patterns of activity (Paton et al, 1998;Hajos et al, 2000;Robbe et al, 2006). An interesting possibility to account for the different action of cannabinoids and opioids on hippocampal activity is that these two neuromodulators may act on distinct types of interneurons.…”

Effects of μ-Opioid Receptor Modulation on GABAB Receptor Synaptic Function in Hippocampal CA1

“…Because the effects of MOR activity in hippocampal CA1 were proposed to act through effects on inhibitory interneurons (Lupica and Dunwiddie 1991), the effects of MOR activation on excitatory activity in CA1 should be occluded in the absence of synaptic inhibition. This hypothesis was tested by blocking GABA B receptors with CGP 55845 and then examining the effect of DAMGO in complete suppression of GABA receptor function.…”

“…In support of a mechanism of action for MOR activation within the dendrites of CA1 pyramidal cells, voltage-sensitive dye (VSD) studies showed that MOR activation can enhance paired-pulse excitatory activity within the dendrites of CA1 pyramidal neurons and that this enhancement was the result of an inhibition of ␥-aminobutyric acid type A (GABA A ) IPSPs (McQuiston and Saggau 2003). However, MOR activation in CA1 pyramidal cells was also shown to inhibit GABA B IPSPs (Lupica and Dunwiddie 1991), but the site of action for MOR effects on GABA B synaptic inhibition along the somatodendritic domain of CA1 pyramidal cells has not been examined. Therefore in an effort to determine the anatomical location of MOR suppression of GABA B synaptic function in hippocampal CA1, we isolated GABA B synaptic function from GABA A synaptic activity with bicuculline (50 M) and used VSD imaging to simultaneously measure changes in inhibitory and excitatory synaptic events in all layers of CA1 after the application of the MOR agonist DAMGO.…”