Pharmacologic characterization of the receptor mediating the hypnotic action of dexmedetomidine.

Abstract

The anesthetic-reducing property of medetomidine far exceeds that seen with other alpha 2-adrenergic agonists (e.g., clonidine). This study examined whether medetomidine possesses hypnotic-anesthetic actions. Dexmedetomidine (the d-enantiomer of medetomidine) induced loss of righting reflex in rats (i.e., hypnosis) at doses greater than 100 micrograms/kg i.p.; sleep-time was dose-dependent up to 1000 micrograms/kg i.p. The l-enantiomer of medetomidine (MPV-1441) did not induce hypnosis even when administered up to 30,000 micrograms/kg i.p. The centrally-active alpha 2-receptor antagonists, atipamezole (MPV-1248) and idazoxan, dose-dependently decreased the hypnotic action of dexmedetomidine. The peripherally-active alpha 2-receptor antagonist, DG-5128, did not reduce dexmedetomidine-induced hypnosis. The stereospecificity of dexmedetomidine's hypnotic action and its dose-dependent attenuation by alpha 2-antagonists confirmed the involvement of alpha 2-receptors in this effect. The finding that only alpha 2-antagonists with central activity attenuate the hypnotic action of dexmedetomidine, suggests that the mediating alpha 2-receptor is located in the central nervous system. In summary, this study suggests that dexmedetomidine induces hypnosis in rats by activating central alpha 2-adrenergic receptors. This study also suggests that alpha 2-antagonists can be used to reverse the hypnotic effects of dexmedetomidine.