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.
Keywords: Analgesic effect; Dexmedetomidine; Dexmedetomidine (Chem CID: 5311068); HCN currents; α(2)-adrenergic receptor agonist.
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