Mechanisms of delta opioid receptor inhibition of parallel fibers-purkinje cell synaptic transmission in the mouse cerebellar cortex.

Delta opioid receptors (DORs) are widely expressed throughout the central nervous system, including the cerebellum, where they play a regulatory role in neurogenesis. In the cerebellar cortex, Purkinje cells (PCs), the sole output neurons, receive glutamatergic synaptic input from parallel fibers (PFs)-the axonal extensions of granule cells-forming PF-PC synapses. However, the precise distribution of DORs within these synapses and their impact on synaptic transmission remain unclear. In this study, we utilized whole-cell patch-clamp recordings and neuropharmacological approaches to explore the effects of DORs activation on PF-PC synaptic transmission in the mouse cerebellar cortex and to elucidate the underlying mechanisms. We found that the selective DORs agonist DPDPE significantly reduced the amplitude and area under the curve (AUC) of PF-PC evoked excitatory postsynaptic currents (eEPSCs), accompanied by an increase in the paired-pulse ratio (PPR). This inhibitory effect was blocked by the DORs antagonist Naltrindole. Additionally, DPDPE decreased the frequency of PF-PC miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude, indicating a presynaptic site of action. When the protein kinase A (PKA) inhibitor PKI was added to the internal solution of the recording electrode, it did not alter the DPDPE-induced suppression of PF-PC mEPSC frequency. However, this suppression was reversed by KT5720, a cell-permeable PKA-specific inhibitor. These findings suggest that DPDPE inhibits PF-PC synaptic transmission through the preferential activation of presynaptic DORs, with this process being dependent on the cyclic adenosine monophosphate (cAMP)-PKA signaling pathway.