The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists.

Linden, Anni-Maija and Aller, M. Isabel and Leppa, Elli and Vekovischeva, Olga and Aitta-Aho, Teemu and Veale, Emma L. and Mathie, Alistair and Rosenberg, Per and Wisden, William and Korpi, Esa R. (2006) The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists. Journal of Pharmacology and Experimental Therapeutics, 317 (2). pp. 615-626. ISSN 0022-3565. (The full text of this publication is not available from this repository)

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Official URL
http://dx.doi.org/10.1124/jpet.105.098525

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.

Item Type: Article
Subjects: Q Science > QP Physiology (Living systems)
Divisions: Faculties > Science Technology and Medical Studies > Medway School of Pharmacy
Depositing User: Alistair Mathie
Date Deposited: 16 Mar 2009 09:03
Last Modified: 11 Jun 2014 10:53
Resource URI: http://kar.kent.ac.uk/id/eprint/5628 (The current URI for this page, for reference purposes)
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