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NEUROPHARMACOLOGY

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

Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland (A.-M.L., E.L., O.V., T.A., E.R.K.); Department of Clinical Neurobiology, University of Heidelberg, Heidelberg, Germany (M.I.A., W.W.); Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom (E.L.V., A.M.); and Department of Anesthesiology and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland (P.R.)

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 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.

Address correspondence to: Dr. Esa R. Korpi, Institute of Biomedicine, Pharmacology, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. E-mail: esa.korpi{at}helsinki.fi

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