The in Vivo Contributions of Task-1-containing Channels to the Actions of Inhalation Anesthetics, the Alpha(2) Adrenergic Sedative Dexmedetomidine, and Cannabinoid Agonists.
From: Institute of Biomedicine, Pharmacology, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
The Journal of pharmacology and experimental therapeutics
- Publish Date: May 2006
- ISSN: 0022-3565
- Volume: 317
- Issue: 2
- Pages: 615-26
- Medium: Print
- Language: English
- Citation (JAMA): Linden Anni-Maija, Aller M Isabel, Leppä Elli, et al. The in Vivo Contributions of Task-1-containing Channels to the Actions of Inhalation Anesthetics, the Alpha(2) Adrenergic Sedative Dexmedetomidine, and Cannabinoid Agonists.. J. Pharmacol. Exp. Ther. May 2006;317:615-26
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.
Mesh Headings (Keywords): Anesthetics, Inhalation, Animals, Behavior, Animal, Benzoxazines, Brain, Dexmedetomidine, Female, In Situ Hybridization, Male, Mice, Mice, Knockout, Morpholines, Naphthalenes, Nerve Tissue Proteins, Potassium Channels, Tandem Pore Domain, Receptors, Adrenergic, alpha-2, Receptors, Cannabinoid
Check for Full Text / PubMed Unique Identifier (PMID): 16397088
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