The α2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects


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Abstract

BackgroundThe authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective α2-adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways.Methodsc-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and in situ hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of γ-aminobutyric acid receptor type A (GABAA) receptor antagonist gabazine, or (3) α2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the α2A-adrenoceptor in mice.ResultsDexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, i.e., a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional α2A-adrenoceptors, which do not show a sedative response to dexmedetomidine. Bilateral VLPO lesions attenuated the sedative response to dexmedetomidine, and the dose–response curve to dexmedetomidine was shifted right by gabazine administered systemically or directly into the TMN. VLPO lesions and gabazine pretreatment altered c-Fos expression in the TMN but in not the LC after dexmedetomidine administration, indicating a hierarchical sequence of changes.ConclusionsThe authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine's sedative mechanism involves inhibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.

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