Background and Objectives κ-Opioid receptor (κ-OR) activation is known to play a role in analgesia and central sedation. The purpose of the present study was to examine the effect of the κ-OR agonist, U-50488 (an arylacetamide), on Ca²⁺ channel currents and the signaling proteins involved in acutely isolated rat dorsal root ganglion (DRG) neurons expressing the putative promoter region of the tetrodotoxin-resistant Na⁺ channel (Na_V 1.8) that is known to be involved in pain transmission.

Methods Acutely isolated rat DRG neurons were transfected with cDNA coding for enhanced green fluorescent protein (EGFP), whose expression is driven by the Na_V 1.8 promoter region. Thereafter, the whole-cell variant of the patch-clamp technique was used to record Ca²⁺ channel currents in neurons expressing EGFP.

Results Exposure of EGFP-expressing DRG neurons to U-50488 (0.3–40 μM) led to voltage-independent inhibition of the Ca²⁺ channel currents. The modulation of the Ca²⁺ currents did not appear to be mediated by the Gα protein subfamilies: Gα_i/o, Gα_s, Gα_q/11, Gα₁₄, and Gα_z. Furthermore, dialysis of the hydrolysis-resistant GDP analog, GDP-β-S (1 mM), did not affect the U-50488–mediated blocking effect, ruling out involvement of other G protein subunits. Finally, U-50488 (20 μM) blocked Ca²⁺ channels heterologously expressed in HeLa cells that do not express κ-OR.

Conclusion These results suggest that the antinociceptive actions mediated by U-50488 are likely due to both a direct block of Ca²⁺ channels in sensory neurons as well as G protein modulation of Ca²⁺ currents via κ-OR–expressing neurons.