The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the α2 adrenergic sedative dexmedetomidine, and cannabinoid agonists

被引:70
作者
Linden, AM
Aller, MI
Leppä, E
Vekovischeva, O
Aitta-Aho, T
Veale, EL
Mathie, A
Rosenberg, P
Wisden, W
Korpi, ER
机构
[1] Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland
[2] Heidelberg Univ, Dept Clin Neurobiol, D-6900 Heidelberg, Germany
[3] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London SW7 2AZ, England
[4] Helsinki Univ Hosp, Dept Anesthesiol & Intens Care Med, Helsinki, Finland
基金
英国医学研究理事会;
关键词
D O I
10.1124/jpet.105.098525
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Inhalation anesthetics activate and cannabinoid agonists inhibit TWIK-related acid-sensitive K+ channels (TASK)-1 two-pore domain leak K+ channels in vitro. Many neuromodulators, such as noradrenaline, might also manifest some of their actions by modifying TASK channel activity. Here, we have characterized the basal behavioral phenotype of TASK-1 knockout mice and tested their sensitivity to the inhalation anesthetics halothane and isoflurane, the alpha(2) adrenoreceptor agonist dexmedetomidine, and the cannabinoid agonist WIN55212-2 mesylate [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3,-de]-1,4-benzoxazinyl](1-naphtalenyl)methanone mesylate)]. TASK-1 knockout mice had a largely normal behavioral phenotype. Male, but not female, knockout mice displayed an enhanced acoustic startle response. The knockout mice showed increased sensitivity to thermal nociception in a hot-plate test but not in a tail-flick test. The analgesic, sedative, and hypothermic effects of WIN55212-2 (2-6 mg/kg s.c.) were reduced in TASK-1 knockout mice. These results implicate TASK-1-containing channels in supraspinal pain pathways, in particular those modulated by endogenous cannabinoids. TASK-1 knockout mice were less sensitive to the anesthetic effects of halothane and isoflurane than wild-type littermates, requiring higher anesthetic concentrations to induce immobility as reflected by loss of the tail-withdrawal reflex. Our results support the idea that the activation of multiple background K+ channels is crucial for the high potency of inhalation anesthetics. Furthermore, TASK-1 knockout mice were less sensitive to the sedative effects of dexmedetomidine (0.03 mg/kg s.c.), suggesting a role for the TASK-1 channels in the modulation of function of the adrenergic locus coeruleus nuclei and/or other neuronal systems.
引用
收藏
页码:615 / 626
页数:12
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