Dexmedetomidine produced analgesic effect via inhibition of HCN currents.

The purpose of this study was to investigate the mechanism by which systemic dexmedetomidine exerts analgesic effect and examine effect of dexmedetomidine on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels currents. The experiments were performed on C57BL/6 J and HCN1 knockout mice. The analgesic effects of intraperitoneal dexmedetomidine (10-40 μg/kg) were measured by a tail-flick test. Whole-cell clamp recordings were used to examine the properties of cloned HCN subunit currents expressed in HEK 293 cells under control condition and dexmedetomidine administration (0.1-10 μM). Injection of dexmedetomidine caused a clear time and dose-related increase in the tail-flick latency of both wild type and knockout mice. Compared with the wild type group, the MPE (maximum possible effect) of tail-flick latency induced by 30 μg/kg and 40 μg/kg dexmedetomidine in knockout mice was significantly lower. The α2-adrenergic receptor antagonist yohimbine (5 μg/kg) reduced the MPE of dexmedetomidine (30 μg/kg) both in wild type and knockout mice. Dexmedetomidine(0.1-10 μM) inhibited HCN1 and HCN2 channel currents in HEK 293 cells, caused a decrease of maximal currents, an increase of inhibition rate of hyperpolarization-activated currents (Ih), and a negative shift in V1/2. We conclude that dexmedetomidine produces a dose-dependently analgesic effect, and the effect is likely due to the inhibition of HCN currents.