A Novel Carbamoyloxy Arylalkanoyl Arylpiperazine Compound (SKL-NP) Inhibits Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channel Currents in Rat Dorsal Root Ganglion Neurons

Abstract

In this study, we determined mode of action of a novel carbamoyloxy arylalkanoyl arylpiperazine compound (SKL-NP) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents ($I_h$) that plays important roles in neuropathic pain. In small or medium-sized dorsal root ganglion (DRG) neurons (< $40{\mu}m$ in diameter) exhibiting tonic firing and prominent $I_h$, SKL-NP inhibited $I_h$ and spike firings in a concentration dependent manner ($IC_{50}=7.85{\mu}M$). SKL-NP-induced inhibition of $I_h$ was blocked by pretreatment of pertussis toxin (PTX) and N-ethylmaleimide (NEM) as well as 8-Br-cAMP, a membrane permeable cAMP analogue. These results suggest that SKL-NP modulates $I_h$ in indirect manner by the activation of a Gi-protein coupled receptor that decreases intracellular cAMP concentration. Taken together, SKL-NP has the inhibitory effect on HCN channel currents ($I_h$) in DRG neurons of rats.