Halothane-induced Hypnosis Is Not Accompanied by Inactivation of Orexinergic Output in Rodents

Abstract

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 we showed that isoflurane and sevoflurane inhibit orexinergic neurons, delaying reintegration of sensory perception as denoted by emergence. Herein we 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 due to loss of orexinergic neurons, did not show delayed emergence from halothane. Conclusion 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.

Modulation of Fronto-Cortical Activity by Modafinil: A Functional Imaging and Fos Study in the Rat

“…Similarly, as also mentioned previously, halothane (1.5%) was found to preserve the spinal and supraspinal patterns of c-fos induced by mechanical stimulations (Novikova et al, 2004). Halothane anesthesia also did not alter Fos expression in orexin-containing neurons compared with spontaneously breathing animals over 2 h exposure (Gompf et al, 2009). Although these results do not permit to rule out an effect of anesthesia on Fos induction in our study, they however argue against a role of anesthesia as a main confounding factor in the interpretation of results.…”

Distinctive Recruitment of Endogenous Sleep-promoting Neurons by Volatile Anesthetics and a Nonimmobilizer

“…67-69 Halothane has also been shown to cause less depression of the cortical electroencephalogram compared to isoflurane, 70,71 which may be caused in part, by halothane's persistent activation of the wake-active locus coeuruleus and orexinergic neurons. 72 Consequently, halothane's failure to stimulate GABAergic MnPO neurons is not entirely surprising.…”

“…55 Different anesthetics also undoubtedly act on distinct molecular and anatomical components of sleep circuitry to varying degrees. 55,72,78-80 From a functional standpoint, the volatile anesthetics distinguish themselves from natural sleep by their accumulation of rapid eye movement sleep debt and inability to relieve pre-existing rapid eye movement debt during exposure. 81-83 Though sleep and anesthetic induced unconsciousness are clearly distinct states, our findings are consistent with a role for an endogenous sleep-promoting GABAergic neuronal population in the VLPO in genesis of volatile general anesthetic hypnosis but fail to confirm an invariant contribution of MnPO neuronal populations.…”

Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia

“…Delivery of NE directly to the nucleus basalis, another node in sleep-wake circuits and one of many regions that receive NE innervation from the LC, produces transient microarousals in desflurane-anesthetized rats, supporting a role for NE in emergence functions (7). Although elimination of LC-NE discharge is not necessary for volatile anesthetic action (15,30), increases in LC activity and central NE levels after cessation of halothane anesthesia have been documented (31,32). In addition, during halothane anesthesia, LC discharge rate has been positively correlated with arousal-related changes in cortical and hippocampal EEG (8,33).…”