Orexinergic neurons and barbiturate anesthesia

Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates OX A and B significantly decreased pentobarbital, thiopental and phenobarbital anesthesia times by 15-40%. SB-334867-A increased thiopental-induced anesthesia time by approximately by 40%, and reversed the decrease produced by OX A. In vitro, all anesthetic barbiturates inhibited OX-evoked norepinephrine release with clinically relevant IC50 values. A GABA(A) antagonist, bicuculline, did not modify the inhibitory effects of thiopental and the GABA(A) agonist, muscimol, did not inhibit norepinephrine release. In addition there was no interaction of barbiturates with either OX, or OX2 receptors. Collectively our data suggest that orexinergic neurons may be an important target for barbiturates, and GABA(A), OX1 and OX2 receptors may not be involved in this interaction. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.