The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists.
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.
Linden
Anni-Maija
AM
Institute of Biomedicine, Pharmacology, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
Aller
M Isabel
MI
Leppä
Elli
E
Vekovischeva
Olga
O
Aitta-Aho
Teemu
T
Veale
Emma L
EL
Mathie
Alistair
A
Rosenberg
Per
P
Wisden
William
W
Korpi
Esa R
ER
D058647:Adrenergic alpha-2 Receptor Agonists; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D020927:Dexmedetomidine / Q000494:pharmacology*; D005260:Female; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology*
D058647:Adrenergic alpha-2 Receptor Agonists; D018685:Anesthetics, Inhalation; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D020927:Dexmedetomidine