title: 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 knockout (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 co-packaged 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 on inhibition of adrenergic neurotransmission.
authors.affiliation: Department of Anesthesiology and Critical Care, Center for Sleep and Circadian Neurobiology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Frances Y
authors.initials: FY
authors.lastname: Hu
authors.forename: George M
authors.initials: GM
authors.lastname: Hanna
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Feras
authors.initials: F
authors.lastname: Mardini
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Wyner
authors.forename: Max B
authors.initials: MB
authors.lastname: Kelz
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D020927:Dexmedetomidine / Q000633:toxicity*; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency* / Q000235:genetics; D004342:Drug Hypersensitivity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006993:Hypnotics and Sedatives / Q000633:toxicity*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014835:Volatilization
chemical_list: D018685:Anesthetics, Inhalation; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D004299:Dopamine beta-Hydroxylase