δ Opioid Receptor Modulation of Several Voltage-Dependent Ca2+Currents in Rat Sensory Neurons

Abstract

Endogenous enkephalins and δ opiates affect sensory function and pain sensation by inhibiting synaptic transmission in sensory circuits via delta opioid receptors (DORs). DORs have long been suspected of mediating these effects by modulating voltage-dependent Ca²⁺ entry in primary sensory neurons. However, not only has this hypothesis never been validated in these cells, but in fact several previous studies have only turned up negative results. By using whole-cell current recordings, we show that the δ enkephalin analog [d-Ala²,d-Leu⁵]-enkephalin (DADLE) inhibits, via DORs, L-, N-, P-, and Q-high voltage-activated Ca²⁺ channel currents in cultured rat dorsal root ganglion (DRG) neurons. The percentage of responding cells was remarkably high (75%) within a novel subpopulation of substance P-containing neurons compared with the other cells (18–35%). DADLE (1 μm) inhibited 32% of the total barium current through calcium channels (I_Ba). A δ (naltrindole, 1 μm), but not a μ (β-funaltrexamine, 5 μm), antagonist prevented the DADLE response, whereas a DOR-2 subtype (deltorphin-II, 100 nm), but not a DOR-1 (DPDPE, 1 μm), agonist mimicked the response. L-, N-, P-, and Q-type currents contributed, on average, 18, 48, 14, and 16% to the total I_Ba and 19, 50, 26, and 20% to the DADLE-sensitive current, respectively. The drug-insensitive R-type current component was not affected by the agonist. This work represents the first demonstration that DORs modulate Ca²⁺entry in sensory neurons and suggests that δ opioids could affect diverse Ca²⁺-dependent processes linked to Ca²⁺ influx through different high-voltage-activated channel types.