title: Dexmedetomidine produced analgesic effect via inhibition of HCN currents.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Ying-cong
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Qing-tao
authors.initials: QT
authors.lastname: Meng
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: xiazhongyuanmz@hotmail.com.
authors.forename: Zhong-yuan
authors.initials: ZY
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Xiang-dong
authors.initials: XD
authors.lastname: Chen
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D020927:Dexmedetomidine / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology
chemical_list: D018712:Analgesics, Non-Narcotic; C578666:Hcn1 protein, mouse; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D020927:Dexmedetomidine
keywords: Analgesic effect; Dexmedetomidine; Dexmedetomidine (Chem CID: 5311068); HCN currents; α(2)-adrenergic receptor agonist