The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects - PubMed (original) (raw)

The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects

Laura E Nelson et al. Anesthesiology. 2003 Feb.

Abstract

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.

PubMed Disclaimer

Cited by

Dexmedetomidine: What's New for Pediatrics? A Narrative Review.
Mahmoud M, Barbi E, Mason KP. Mahmoud M, et al. J Clin Med. 2020 Aug 24;9(9):2724. doi: 10.3390/jcm9092724. J Clin Med. 2020. PMID: 32846947 Free PMC article. Review.
Nitrous oxide-induced slow and delta oscillations.
Pavone KJ, Akeju O, Sampson AL, Ling K, Purdon PL, Brown EN. Pavone KJ, et al. Clin Neurophysiol. 2016 Jan;127(1):556-564. doi: 10.1016/j.clinph.2015.06.001. Epub 2015 Jun 10. Clin Neurophysiol. 2016. PMID: 26118489 Free PMC article.
Dexmedetomidine Supported Office Based Genioplasty: A Pilot Study.
Kumar P, Priya K, Kirti S, Johar S, Singh V. Kumar P, et al. J Maxillofac Oral Surg. 2015 Sep;14(3):750-3. doi: 10.1007/s12663-014-0733-6. Epub 2015 Jan 6. J Maxillofac Oral Surg. 2015. PMID: 26225072 Free PMC article.
A Comparison of the Sedative Effect of Dexmedetomidine and Midazolam on Patients Undergoing Gastrointestinal Endosonography Outside the Operating Room.
Ghomeishi A, Akhondzadeh R, Baghbanian R, Mahmoudi K, Bakhtiari N. Ghomeishi A, et al. Anesth Pain Med. 2023 May 1;13(3):e109721. doi: 10.5812/aapm-109721. eCollection 2023 Jun. Anesth Pain Med. 2023. PMID: 38021337 Free PMC article.
Society of anesthesia and sleep medicine: proceedings of 2012 annual meeting.
Kaw R, Mokhlesi B, Chung F, Gay P, Bolden N, Hillman D. Kaw R, et al. Sleep Breath. 2013 Dec;17(4):1333-9. doi: 10.1007/s11325-013-0843-2. Epub 2013 May 15. Sleep Breath. 2013. PMID: 23673871

The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects - PubMed (original) (raw)