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doi: 10.1097/ALN.0b013e3182700c93
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Noradrenergic Trespass in Anesthetic and Sedative States

Sanders, Robert D. B.Sc., M.B.B.S., Ph.D., F.R.C.A.*; Maze, Mervyn M.B.Ch.B., F.R.C.P., F.R.C.A., F.Med.Sci.

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“If substantiated, suppression of noradrenergic signaling would emerge as a core component of anesthesia to prevent the awareness of surgery.”
Fig. 1
Fig. 1
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In this issue of ANESTHESIOLOGY, Hu et al.1 delve into the mechanisms of hypnotic action of potent volatile anesthetic agents as well as dexmedetomidine; these data build upon previous work from this and other laboratories that collectively provide insights that may affect how these agents are used in clinical practice.2–8 Using mice that lack the dopamine-β-hydroxylase (DβH) gene and are therefore incapable of synthesizing noradrenaline and adrenaline throughout the organism, the authors confirm their previous findings of enhanced sensitivity to, or delayed emergence from, volatile anesthetic agents.2 In addition, they corroborate that α2 adrenergic agonists (of which dexmedetomidine is the prototype in contemporary clinical practice) are capable of producing a hypnotic response, established both by behavioral and electrophysiological paradigms, in these mutated mice. Further, they show that DβH knockout mice are remarkably sensitive to dexmedetomidine, using more sophisticated electrophysiologic endpoints than the previously reported loss of righting reflex.1 Ultimately Hu et al.’s interpretation of their data challenge the Nelson model of anesthetic action for dexmedetomidine,7 but not GABAergic agents,5,6,8 which centers on suppression of noradrenergic signaling from the locus ceruleus (fig. 1). Earlier, these investigators established that both GABAergic agents and dexmedetomidine activate the ventrolateral preoptic nucleus, the endogenous sleep switch; however, they proposed that dexmedetomidine appeared to do this by inhibiting noradrenergic input from the locus ceruleus into the ventrolateral preoptic nucleus while GABAergic agents act directly on ventrolateral preoptic nucleus itself.
Mice that lack a critical gene, such as DβH (DβH−/− mice), survive the absence of critical neurotransmitters by adaptive changes. In DβH −/−- mice, there is a significant increase in the catecholamine dopamine, the substrate for the absent enzyme, which is also capable of binding to and activating both adrenergic and noradrenergic receptors, although with much lower affinity.9 The authors acknowledge this possibility, and devise a “reversal” experiment in which adrenergic and noradrenergic ligands are administered centrally, using a pharmacological strategy developed by one of the authors1; this normalizes the sensitivity of DβH −/− mice to that seen in the wild-type control mice. However, to establish that this is solely due to replenishing the missing ligands, it would be necessary to show that this pharmacologic strategy does not nonspecifically alter sensitivity in wild-type mice that already have a full complement of catecholamines. In the absence of such data, one cannot conclude that pharmacological restoration of noradrenaline and/or adrenaline in the DβH−/− mice is the reason for normalization of the sedative response to dexmedetomidine.
Regarding the overexpression of dopamine, by binding and activating the D2 dopaminergic receptor subtype, this catecholamine is capable of decreasing the minimum alveolar concentration for halothane10; whether or not a similar alteration in sensitivity obtains for α2 agonists is known. Remarkably, others have shown enhanced reversal of the hypnotic response to isoflurane with increased dopaminergic signaling.11 Both alternatives need to be directly addressed if one is to conclude that the enhanced sensitivity is due to the missing ligands, rather than due to the increased expression of dopamine.
Notwithstanding these issues, data provided in this article contribute to an impressive body of work from Kelz’s laboratory, which seeks to explain communication between various brain nuclei and neurotransmitter systems for the induction and emergence from volatile and intravenous hypnotic agents.1–4 The locus ceruleus, a collection of noradrenergic neurons in the brainstem, has been considered to be pivotal for inducing the hypnotic response to dexmedetomidine based upon a series of experiments in which the agonist induced a hypnotic response when delivered discretely into that nucleus but not when administered 2 mm away.12,13 These findings were corroborated by data from experiments in which the hypnotic effects of systemically administered dexmedetomidine was blocked when an α2 adrenoceptor antagonist was delivered into the locus ceruleus.7 Both, because the distribution of the injectate into either site was not established, and, because of the periventricular location of this nucleus, it is conceivable that the α2 agonist may have initiated the hypnotic response on 2A adrenoceptors14 at more distant nonnoradrenergic neurons.15 Indeed another recent study showed that knockout of the α2A adrenoceptor on noradrergic neurons did not affect the hypnotic response to the α2 agonist medetomidine.15 Nevertheless, the critical requirement for a reduction in the firing of the locus ceruleus neurons for dexmedetomidine’s hypnotic action are neither supported not refuted by the data provided by Hsu et al. (fig. 1).1,15
Intriguingly, and despite significant research, the role of noradrenergic signaling in natural arousal mechanisms in the brain remains unclear. Depletion of central noradrenaline or adrenaline does not affect the sleep–wake cycle, suggesting there is overlap and redundancy of neurotransmitters to control arousal states. However, noradrenergic signaling is suppressed during sleep perhaps because it plays a critical role in diverting attention to external stimuli. Suppression of this external surveillance when trying to rest may permit some of the homeostatic functions of sleep such as synaptic downscaling.16 Hence, a defining feature of sleep is that we are unaware of our environment, or disconnected.17 We have recently argued that disconnection is a critical aim of anesthesia, and hypothesized that noradrenaline plays a critical role in maintaining connectedness (the potential for an experience to be triggered by an external stimulus) during anesthesia.17 If substantiated, suppression of noradrenergic signaling would emerge as a core component of anesthesia to prevent the awareness of surgery.
Anesthetics that act on GABAergic agents type A receptors, such as propofol, pentobarbital, and the volatile anesthetics, exert little effect on noradrenergic signaling (fig. 1).5,6,8 Nevertheless, attenuation of noradrenergic signaling does increase sensitivity to GABAergic agents (as Hu et al. illustrate). Suppression of noradrenergic signaling does not appear necessary for anesthetic-induced hypnosis (defined as the patient “looking asleep”) paralleling its redundancy in the sleep–wake cycle. However, while the patient may look “asleep,” intact noradrenergic signaling may drive connectedness to the environment explaining why hypnotic doses of anesthesia always do not suppress responses on the isolated forearm technique during surgery.17 As such, noradrenergic signaling may be considered a previously unrecognized trespasser in the anesthetic state, which may promote awareness during GABAergic hypnosis.
Delaying connectedness on emergence from hypnosis may have related consequences such as reducing postoperative and critical care delirium by preventing emergence from hypnosis at a reduced level of consciousness. This state can be considered akin to “sleep inertia” in which subjects awake confused from nonrapid eye-movement sleep; similarly, delirious patients may not have sufficient conscious cognitive processing to interact appropriately with the environment.17,18 Delaying connectedness by suppressing noradrenergic activity may be a way to prevent this. In turn, this may explain why dexmedetomidine decreased emergence delirium after volatile anesthesia, agitation in pediatric patients with sleep apnea, and delirium in the mechanically ventilated patients.19–22 To the perioperative utility of α2 agonists for mitigating pain, nausea, inflammation, and organ injury can now be added its putative effects on delaying connectedness. Translational studies building on the important preclinical findings by Kelz and others may edge us closer to improvements in clinical care by identifying other trespassing neurotransmitters in the anesthetic or sedated state, which can be modulated to improve perioperative and critical care outcomes.23
Robert D. Sanders, B.Sc., M.B.B.S., Ph.D., F.R.C.A.,* Mervyn Maze, M.B.Ch.B., F.R.C.P., F.R.C.A., F.Med.Sci.†
*Wellcome Department of Imaging Neuroscience, Univeristy College London, London, United Kingdom. †Department of Anesthesia & Perioperative Care, University of California, San Francisco, San Francisco, California.
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12. Correa-Sales C, Nacif-Coelho C, Reid K, Maze M. Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat. J Pharmacol Exp Ther. 1992;263:1046–9

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14. Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM, Maze M, Limbird LE. Substitution of a mutant alpha2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci USA. 1997;94:9950–5

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17. Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness ≠ unconsciousness. ANESTHESIOLOGY. 2012;116:946–59

18. Sanders RD. Hypothesis for the pathophysiology of delirium: Role of baseline brain network connectivity and changes in inhibitory tone. Med Hypotheses. 2011;77:140–3

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22. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. . Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009;301:489–99

23. Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, Herr DL, Maze M, Ely EW. MENDS investigators: effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38

24. Sanders RD, Hussell T, Maze M. Sedation & immunity: Optimisation for critically ill patients. Intense Times. 2010;9:2–5

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