The in Vivo Contributions of TASK-1-Containing Channels to the Actions of Inhalation Anaesthetics, the {alpha} 2 Adrenergic Sedative Dexmedetomidine and Cannabinoid Agonists

A. M. Linden, M. I. Aller, O. Y. Vekovischeva, T. Aitta-Aho, E. L. Veale, A. Mathie, P. Rosenberg, William Wisden, E. R. Korpi

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    Abstract

    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.

    Original languageEnglish
    Pages (from-to)615-626
    Number of pages11
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume317
    DOIs
    Publication statusPublished - 2006

    Keywords

    • DOMAIN K+ CHANNEL
    • POTASSIUM CHANNEL
    • GENERAL-ANESTHESIA
    • KNOCKOUT MICE
    • TASK CHANNELS
    • RECEPTOR
    • ANANDAMIDE
    • CONDUCTANCE
    • MODULATION
    • NEURONS

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