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 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.
Footnotes
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This work was supported by the German Research Council (Grant DFG WI 1951/1-2) (to W.W.), by Volkswagen Stiftung (Grant I/78 554) (to W.W.), by the Academy of Finland (to E.R.K.), and by the Sigrid Juselius Foundation (to E.R.K.).
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doi:10.1124/jpet.105.098525.
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ABBREVIATIONS: TASK, TWIK-related acid-sensitive K+ channel; TWIK, tandem P domain weak inwardly rectifying K+ channels; K2P, two-pore-domain background K+; WIN55212-2 mesylate, R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphtalenyl)methanone mesylate); PPI, prepulse inhibition; LORR, loss of righting reflex; LOTW, loss of tail withdrawal reflex; GTPγ[35S], guanosine-5′-O-(3-[35S]thio)-triphosphate; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; ANOVA, analysis of variance; MAC, minimum alveolar concentration; TREK, TWIK-related K+ channel.
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↵1 Current affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland.
- Received November 10, 2005.
- Accepted January 4, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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