delta opioid receptor modulation of several voltage-dependent Ca2+ currents in rat sensory neurons

Endogenous enkephalins and delta opiates affect sensory function and pain s ensation by inhibiting synaptic transmission in sensory circuits via delta opioid receptors (DORs). DORs have long been suspected of mediating these e ffects by modulating voltage-dependent Ca2+ entry in primary sensory neuron s. However, not only has this hypothesis never been validated in these cell s, but in fact several previous studies have only turned up negative result s. By using whole-cell current recordings, we show that the d enkephalin an alog [D-Ala(2), D-Leu(5)]-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 remark ably high (75%) within a novel subpopulation of substance P-containing neur ons compared with the other cells (18-35%). DADLE (1 mu M) inhibited 32% of the total barium current through calcium channels (I-Ba). A delta (naltrin dole, 1 mu M), but not a mu (beta-funaltrexamine, 5 mu M), antagonist preve nted the DADLE response, whereas a DOR-2 subtype (deltorphin-II, 100 nM), b ut not a DOR-1 (DPDPE, 1 mu M), agonist mimicked the response. L-, N-, P-, and Q-type currents contributed, on average, 18, 48, 14, and 16% to the tot al I-Ba and 19, 50, 26, and 20% to the DADLE-sensitive current, respectivel y. The drug-insensitive R-type current component was not affected by the ag onist. This work represents the first demonstration that DORs modulate Ca2 entry in sensory neurons and suggests that d opioids could affect diverse Ca2+-dependent processes linked to Ca2+ influx through different high-volta ge-activated channel types.