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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.

SUBMITTER: Lazarenko RM

PROVIDER: S-EPMC2910363 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current.

Lazarenko Roman M RM Fortuna Michal G MG Shi Yingtang Y Mulkey Daniel K DK Takakura Ana C AC Moreira Thiago S TS Guyenet Patrice G PG Bayliss Douglas A DA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100701 27

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 br ...[more]

PMID: 20610767

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Project description:The medullary ventral respiratory column (VRC) of neurons is essential for respiratory motor pattern generation; however, the functional connections among these cells are not well understood. A rostral extension of the VRC, including the retrotrapezoid nucleus/parafacial region (RTN-pF), contains neurons responsive to local perturbations of CO(2)/pH. We addressed the hypothesis that both local RTN-pF interactions and functional connections from more caudal VRC compartments--extending from the Bötzinger and pre-Bötzinger complexes to the ventral respiratory group (Böt-VRG)--influence the respiratory modulation of RTN-pF neurons and their responses to central chemoreceptor and baroreflex activation. Spike trains from 294 RTN-pF and 490 Böt-VRG neurons were monitored with multielectrode arrays along with phrenic nerve activity in 14 decerebrate, vagotomized cats. Overall, 214 RTN-pF and 398 Böt-VRG neurons were respiratory modulated; 124 and 95, respectively, were cardiac modulated. Subsets of these neurons were tested with sequential, selective, transient stimulation of central chemoreceptors and arterial baroreceptors; each cell's response was evaluated and categorized according to the change in firing rate (if any) following the stimulus. Cross-correlation analysis was applied to 2,884 RTN-pF?RTN-pF and 8,490 Böt-VRG?RTN-pF neuron pairs. In total, 174 RTN-pF neurons (59.5%) had significant features in short-time scale correlations with other RTN-pF neurons. Of these, 49 neurons triggered cross-correlograms with offset peaks or troughs (n = 99) indicative of paucisynaptic excitation or inhibition of the target. Forty-nine Böt-VRG neurons (10.0%) were triggers in 74 Böt-VRG?RTN-pF correlograms with offset features, suggesting that Böt-VRG trigger neurons influence RTN-pF target neurons. The results support the hypothesis that local RTN-pF neuron interactions and inputs from Böt-VRG neurons jointly contribute to respiratory modulation of RTN-pF neuronal discharge patterns and promotion or limitation of their responses to central chemoreceptor and baroreceptor stimulation.

Dataset Information

Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current.

Publications

Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current.

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