The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects.
BACKGROUND
The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective alpha -adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways.


METHODS
c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of gamma-aminobutyric acid receptor type A (GABA ) receptor antagonist gabazine, or (3) alpha2-adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the alpha -adrenoceptor in mice.


RESULTS
Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, 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 alpha2a-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.


CONCLUSIONS
The 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.
Nelson
Laura E
LE
Department of Anaesthetics, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Lu
Jun
J
Guo
Tianzhi
T
Saper
Clifford B
CB
Franks
Nicholas P
NP
Maze
Mervyn
M
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002452:Cell Count; D020927:Dexmedetomidine / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects
C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011724:Pyridazines; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D007051:Ibotenic Acid; D020927:Dexmedetomidine; C049853:gabazine