title: Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current.
abstract: At surgical depths of anesthesia, inhalational anesthetics cause a loss of motor response to painful stimuli (i.e., immobilization) that is characterized by profound inhibition of spinal motor circuits. Yet, although clearly depressed, the respiratory motor system continues to provide adequate ventilation under these same conditions. Here, we show that isoflurane causes robust activation of CO(2)/pH-sensitive, Phox2b-expressing neurons located in the retrotrapezoid nucleus (RTN) of the rodent brainstem, in vitro and in vivo. In brainstem slices from Phox2b-eGFP mice, the firing of pH-sensitive RTN neurons was strongly increased by isoflurane, independent of prevailing pH conditions. At least two ionic mechanisms contributed to anesthetic activation of RTN neurons: activation of an Na(+)-dependent cationic current and inhibition of a background K(+) current. Single-cell reverse transcription-PCR analysis of dissociated green fluorescent protein-labeled RTN neurons revealed expression of THIK-1 (TWIK-related halothane-inhibited K(+) channel, K(2P)13.1), a channel that shares key properties with the native RTN current (i.e., suppression by inhalational anesthetics, weak rectification, inhibition by extracellular Na(+), and pH-insensitivity). Isoflurane also increased firing rate of RTN chemosensitive neurons in urethane-anesthetized rats, again independent of CO(2) levels. In these animals, isoflurane transiently enhanced activity of the respiratory system, an effect that was most prominent at low levels of respiratory drive and mediated primarily by an increase in respiratory frequency. These data indicate that inhalational anesthetics cause activation of RTN neurons, which serve an important integrative role in respiratory control; the increased drive provided by enhanced RTN neuronal activity may contribute, in part, to maintaining respiratory motor activity under immobilizing anesthetic conditions.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908-0735, USA.
authors.forename: Roman M
authors.initials: RM
authors.lastname: Lazarenko
authors.forename: Michal G
authors.initials: MG
authors.lastname: Fortuna
authors.forename: Yingtang
authors.initials: Y
authors.lastname: Shi
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Mulkey
authors.forename: Ana C
authors.initials: AC
authors.lastname: Takakura
authors.forename: Thiago S
authors.initials: TS
authors.lastname: Moreira
authors.forename: Patrice G
authors.initials: PG
authors.lastname: Guyenet
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002628:Chemoreceptor Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D012125:Respiratory Center / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018685:Anesthetics, Inhalation; D018398:Homeodomain Proteins; C486604:Kcnk13 protein, mouse; C109220:NBPhox protein; D024683:Potassium Channels, Tandem Pore Domain; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007530:Isoflurane