Distinct inhibition of voltage-activated Ca²⁺ channels by δ-opioid agonists in dorsal root ganglion neurons devoid of functional T-type Ca²⁺ currents

Both μ- and δ-opioid agonists selectively inhibit nociception but have little effect on other sensory modalities. Voltage-activated Ca²⁺ channels in the primary sensory neurons are important for the regulation of nociceptive transmission. In this study, we determined the effect of δ-opioid agonists on voltage-activated Ca²⁺ channel currents (I_Ca) in small-diameter rat dorsal root ganglion (DRG) neurons that do and do not bind isolectin B₄ (IB₄). The δ-opioid agonists [d-Pen²,d-Pen⁵]-enkephalin (DPDPE) and deltorphin II produced a greater inhibition of high voltage-activated I_Ca in IB₄-negative than IB₄-positive neurons. Furthermore, DPDPE produced a greater inhibition of N-, P/Q-, and L-type I_Ca in IB₄-negative than IB₄-positive neurons. However, DPDPE had no significant effect on the R-type I_Ca in either type of cells. We were surprised to find that DPDPE failed to inhibit either the T-type or high voltage-activated I_Ca in all the DRG neurons with T-type I_Ca. Double immunofluorescence labeling showed that the majority of the δ-opioid receptor-immunoreactive DRG neurons had IB₄ labeling, while all DRG neurons immunoreactive to δ-opioid receptors exhibited Cav_3.2 immunoreactivity. Additionally, DPDPE significantly inhibited high voltage-activated I_Ca in Tyrode's or N-methyl-d-glucamine solution but not in tetraethylammonium solution. This study provides new information that δ-opioid agonists have a distinct effect on voltage-activated Ca²⁺ channels in different phenotypes of primary sensory neurons. High voltage-activated Ca²⁺ channels are more sensitive to inhibition by δ-opioid agonists in IB₄-negative than IB₄-positive neurons, and this opioid effect is restricted to DRG neurons devoid of functional T-type Ca²⁺ currents.