Halothane-induced hypnosis is not accompanied by inactivation of orexinergic output in rodents.
BACKGROUND
One underexploited property of anesthetics is their ability to probe neuronal regulation of arousal. At appropriate doses, anesthetics reversibly obtund conscious perception. However, individual anesthetic agents may accomplish this by altering the function of distinct neuronal populations. Previously the authors showed that isoflurane and sevoflurane inhibit orexinergic neurons, delaying reintegration of sensory perception as denoted by emergence. Here the authors study the effects of halothane. As a halogenated alkane, halothane differs structurally, has a nonoverlapping series of molecular binding partners, and differentially modulates electrophysiologic properties of several ion channels when compared with its halogenated ether relatives.


METHODS
c-Fos immunohistochemistry and in vivo electrophysiology were used to assess neuronal activity. Anesthetic induction and emergence were determined behaviorally in narcoleptic orexin/ataxin-3 mice and control siblings exposed to halothane.


RESULTS
Halothane-induced hypnosis occurred despite lack of inhibition of orexinergic neurons in mice. In rats, extracellular single-unit recordings within the locus coeruleus showed significantly greater activity during halothane than during a comparable dose of isoflurane. Microinjection of the orexin-1 receptor antagonist SB-334867-A during the active period slowed firing rates of locus coeruleus neurons in halothane-anesthetized rats, but had no effect on isoflurane-anesthetized rats. Surprisingly, orexin/ataxin-3 transgenic mice, which develop narcolepsy with cataplexy because of loss of orexinergic neurons, did not show delayed emergence from halothane.


CONCLUSIONS
Coordinated inhibition of hypothalamic orexinergic and locus coeruleus noradrenergic neurons is not required for anesthetic induction. Normal emergence from halothane-induced hypnosis in orexin-deficient mice suggests that additional wake-promoting systems likely remain active during general anesthesia produced by halothane.
Gompf
Heinrich
H
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, Massachusetts, USA.
Chen
Jingqiu
J
Sun
Yi
Y
Yanagisawa
Masashi
M
Aston-Jones
Gary
G
Kelz
Max B
MB
D000768:Anesthesia, General; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002940:Circadian Rhythm; D006221:Halothane / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D018685:Anesthetics, Inhalation; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D014508:Urea; D007530:Isoflurane; D006221:Halothane; D009638:Norepinephrine