Thalamic Microinfusion of Antibody to a Voltage-gated Potassium Channel Restores Consciousness during Anesthesia

Department of Anesthesiology and Perioperative Care, Center for Neurobiology of Learning and Memory, University of California- Irvine, Irvine, California, USA.
Anesthesiology (Impact Factor: 5.88). 05/2009; 110(4):766-73. DOI: 10.1097/ALN.0b013e31819c461c
Source: PubMed


The Drosophila Shaker mutant fruit-fly, with its malfunctioning voltage-gated potassium channel, exhibits anesthetic requirements that are more than twice normal. Shaker mutants with an abnormal Kv1.2 channel also demonstrate significantly reduced sleep. Given the important role the thalamus plays in both sleep and arousal, the authors investigated whether localized central medial thalamic (CMT) microinfusion of an antibody designed to block the pore of the Kv1.2 channel might awaken anesthetized rats.
Male Sprague-Dawley rats were implanted with a cannula aimed at the CMT or lateral thalamus. One week later, unconsciousness was induced with either desflurane (3.6 +/- 0.2%; n = 55) or sevoflurane (1.2 +/- 0.1%; n = 51). Arousal effects of a single 0.5-microl infusion of Kv1.2 potassium channel blocking antibody (0.1- 0.2 mg/ml) or a control infusion of Arc-protein antibody (0.2 mg/ml) were then determined.
The Kv1.2 antibody, but not the control antibody, temporarily restored consciousness in 17% of all animals and in 75% of those animals where infusions occurred within the CMT (P < 0.01 for each anesthetic). Lateral thalamic infusions showed no effects. Consciousness returned on average (+/- SD) 170 +/- 99 s after infusion and lasted a median time of 398 s (interquartile range: 279-510 s). Temporary seizures, without apparent consciousness, predominated in 33% of all animals.
These findings support the idea that the CMT plays a role in modulating levels of arousal during anesthesia and further suggest that voltage-gated potassium channels in the CMT may contribute to regulating arousal or may even be relevant targets of anesthetic action.

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    • "By contrast, central thalamic activity is diminished when subjects are rendered unconscious by general anesthesia (Fiset et al., 1999; White and Alkire, 2003). This relationship has been confirmed by evidence that the effects of anesthesia are reversed in animal models when central thalamus is activated by microinjection of nicotine or an antibody to a voltage-gated potassium channel directly into central thalamus (Alkire et al., 2007, 2009). Central thalamic neurons show phasic as well as tonic patterns of activation . "
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    Dose-Response 07/2011; 9(3):313-31. DOI:10.2203/dose-response.10-017.Mair · 1.22 Impact Factor
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    • "However, the Kcna2 short sleeping phenotype is far from being as dramatic as in Shaker flies, perhaps because of redundancy -there is one Shaker gene in Drosophila, but at least 16 genes code for alpha subunits of voltage-dependent potassium channels in mammals (Misonou and Trimmer 2004, Yuan and Chen 2006). Finally in mice, the injection of an antibody against the kv1.2 potassium channel into the central medial thalamus induces arousal from anesthesia (Alkire et al. 2009). "
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    International Review of Neurobiology 01/2011; 99:213-44. DOI:10.1016/B978-0-12-387003-2.00009-4 · 1.92 Impact Factor
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    • "Conversely neural inertia can be narrowed by genetic manipulation as demonstrated by the effects of the mutant allele Shmns in Drosophila. This result is consistent with work done in rats, which demonstrated that microinjection of an antibody against the Shaker potassium channel (Kv1.2) into the central medial thalamus also reverses deep states of anesthetic-induced hypnosis by abruptly triggering emergence, with signs of return to consciousness, despite ongoing delivery of volatile anesthetics [43]. Near-total collapse of neural inertia in Shaker mutant flies raises concerns of additional anesthetic morbidity. "
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    ABSTRACT: One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.
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