Noradrenergic trespass in anesthetic and sedative states.

945 November 2012 I N 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-βhydroxylase (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, Noradrenergic Trespass in Anesthetic and Sedative States