Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine β-Hydroxylase Knockout Mice

Abstract

BACKGROUND Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. METHODS Using dopamine β-hydroxylase (Dbh−/−) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. RESULTS We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators copackaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh−/− mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh−/− mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh−/− mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. CONCLUSIONS Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend upon inhibition of adrenergic neurotransmission.

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

“…In view of previous findings (6,22), our data indicate that diurnal and stress-induced variations in LC-NE activity may affect clinical responses to anesthetic agents. They also suggest that the use of noradrenergic antagonists in patients undergoing surgical procedures should be strongly considered to optimize the safety and regulation of general anesthesia.…”

“…This confirms a role for NE in endogenous anesthetic emergence in WT subjects, as reported recently in DBH KO mice that do not produce NE. DBH KO mice have hypersensitivity to, and extended emergence times from, multiple volatile anesthetics and dexmedetomidine (6,22); however, those KO studies could not specify whether the adrenergic component involved in emergence was the LC or other brain or peripheral NE systems. Our findings identify the LC as a likely major contributor to the results in these KO studies.…”

“…LC-NE activity can drive waking and is a critical downstream effector site for orexin-mediated sleepwake transitions (13,14). Although inhibition of LC-NE neurons is not required for hypnosis with general anesthetic agents (15), dopamine-β-hydroxylase (DBH) knockout (KO) mice (lacking NE) show hypersensitivity to several forms of general anesthesia (6). Considered together, these results indicate a role for NE systems in anesthesia mechanisms that may be critically regulated by the LC.…”

“…These pathways are important in arousal networks that regulate sleep and waking, among other actions. The locus coeruleus (LC)-norepinephrine (NE) brain system is a key arousal node (5); however, the function of LC-NE neurons in anesthetic emergence has been relatively understudied (6)(7)(8).…”

α2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons

“…45 However, more recent studies have implicated effects of α 2 -AR agonists on non-adrenergic neurons in these actions. 9,46,47 Genetically engineered mice that express α 2A -ARs only in noradrenergic terminals show minimal neurological effects of the α 2 -AR agonist medetomidine, including loss of righting reflex and anesthetic-sparing, in contrast to a strong hypnotic effect in wild-type littermates. 9 In another study in vivo, acute knockdown of α 2A -AR expression in the locus coeruleus failed to affect DEX induced sedation.…”