TY - JOUR T1 - The in Vivo Contributions of TASK-1-Containing Channels to the Actions of Inhalation Anesthetics, the α<sub>2</sub> Adrenergic Sedative Dexmedetomidine, and Cannabinoid Agonists JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 615 LP - 626 DO - 10.1124/jpet.105.098525 VL - 317 IS - 2 AU - Anni-Maija Linden AU - M. Isabel Aller AU - Elli Leppä AU - Olga Vekovischeva AU - Teemu Aitta-aho AU - Emma L. Veale AU - Alistair Mathie AU - Per Rosenberg AU - William Wisden AU - Esa R. Korpi Y1 - 2006/05/01 UR - http://jpet.aspetjournals.org/content/317/2/615.abstract N2 - 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 α2 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. The American Society for Pharmacology and Experimental Therapeutics ER -