Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine β-hydroxylase knockout mice - PubMed (original) (raw)

Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine β-hydroxylase knockout mice

Frances Y Hu et al. Anesthesiology. 2012 Nov.

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.

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Figures

Fig.1

Fig.1

Adrenergic-deficient mice exhibit volatile anesthetic hypersensitivity relative to sibling controls with normal levels of norepinephrine/epinephrine. Symbols respectively depict the fraction of Dbh+/− (n=10, triangles) and _Dbh_−/− (n=12, circles) mice that exhibit a loss of righting reflex (LORR) at each specified anesthetic dose for (A) isoflurane, (C) sevoflurane, and (E) halothane. Solid lines denote the best-fit curves with dashed lines showing 95% confidence interval bracketing the best-fit curves. Bars represent mean ± SEM time lapsed from the termination of anesthetic exposure (shown in A, C, E) until the return of righting reflex (RORR) for _Dbh_−/− (black) and Dbh+/− (colored) mice for (B) isoflurane, (D) sevoflurane, and (F) halothane. Effects of genotype are significant F1,236=46.7, p < 0.0001. Atm: atmosphere; Dbh: dopamine β-hydroxylase.

Fig. 2

Fig. 2

Delayed emergence in _Dbh_−/− mice is not due to a relative volatile anesthetic overdose. (A) Time to LORR in _Dbh_−/− and Dbh+/− mice when each group is exposed to their respective ED95 dose for eliciting LORR. (B) Time until RORR in _Dbh_−/− (black) and Dbh+/− (colored) mice following a 2 hour exposure to each group’s respective volatile anesthetic ED95 (n=12/group). There is a significant effect of genotype on emergence F1,66=12.33, p < 0.0003, but not upon induction F1,66=0.14, p=0.7132. Bars show mean ± SEM; LORR: loss of righting reflex; RORR: return of righting reflex; Sevo: sevoflurane; Iso: isoflurane; Halo: halothane; Dbh: dopamine β-hydroxylase.

Fig. 3

Fig. 3

Loss of adrenergic ligands is sufficient to cause hypersensitivity to dexmedetomidine as assessed by LORR. _Dbh_−/− mice illustrate hypersensitivity relative to Dbh+/− mice in response to varying intravenous doses of dexmedetomidine. (A) Latency to loss of righting reflex and (B) Duration of LORR in _Dbh_−/− (red) and Dbh+/− (blue) mice (n=5–6/group). Significant genotypic effects were found for both latency to F1,35=53.40, p < 0.0001 and duration of F1,35=158.77, p < 0.0001 dexmedetomidine-induced hypnosis. * p < 0.05, ** p < 0.01, and *** p < 0.001 relative to Dbh+/− mouse latency to LORR or duration of LORR times. Bars show mean ± SEM; LORR: loss of righting reflex; Dbh: dopamine β-hydroxylase.

Fig. 4

Fig. 4

CNS-specific rescue of norepinephrine and ephinephrine in adrenergic-deficient mice restores duration of dexmedetomidine-induced hypnosis to control levels. Both the latency to LORR following 50 µg/kg of intravenous dexmedetomidine (A) and the duration of LORR (B) are rescued in _Dbh_−/− mice receiving L-threo-3.4-dihydroxyphenylserine and benserazide rescue treatment (blue) compared to _Dbh_−/− mice that received vehicle treatment (red) (n=4/group). * p < 0.05. Bars show mean ± SEM; CNS: central nervous system; LORR: loss of righting reflex; Dbh: dopamine β-hydroxylase.

Fig. 5

Fig. 5

_Dbh_−/− mice show delayed emergence from dexmedetomidine relative to Dbh+/− mice using a motor-independent electroencephalographic measure. (A) Panel shows a characteristic segmental best-fit (solid line) analysis of sample entropy values calculated from raw electroencephalogram in a control mouse before, during, and after intravenous dexmedetomidine. Raw sample entropy values (circles) were calculated from the electroencephalogram, which were fit with five linear segments to approximate five variables as labeled. Dexmedetomidine was administered intravenously at time=0 as denoted by the arrow. (B) Box plots illustrate sample entropy values along with lower quartile, upper quartile, group minimum and group maximum for pre-drug baseline wakefulness, minimum entropy level, the duration of time at the minimum entropy level, the slope of sample entropy recovery that defines emergence, and sample entropy post-dexmedetomidine emergence for Dbh+/− (n=12) and _Dbh_−/− (n=8) mice as computed from right frontal-left frontal, right occipital-left occipital, and left frontal-left occipital leads. * denotes p < 0.05 in _Dbh_−/− mice relative to Dbh+/− mice. Dbh: dopamine β-hydroxylase.

Fig 6

Fig 6

Adrenergic-deficient mice show no significant differences from sibling controls with respect to motor tone following intravenous dexmedetomidine administration. Box plots depict integrated electromyographic intensity (normalized to percentage of maximum during wakefulness) along with lower quartile, upper quartile, group minimum, and group maximum for (A) pre-drug baseline wakefulness, (B) minimum integrated electromyogram values, (C) the duration of time at the minimum integrated electromyogram values, (D) the slope of integrated electromyogram recovery, and (E) stabilized integrated electromyogram values post-dexmedetomidine emergence in Dbh+/− (n=12) and _Dbh_−/− (n=8) mice. * denotes p < 0.05 in _Dbh_−/− mice relative to Dbh+/− mice. iEMG: integrated electromyogram; Dbh: dopamine β-hydroxylase.

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