Sevoflurane Directly Excites Locus Coeruleus Neurons of Rats

Abstract

Background Sevoflurane, an anesthetic showing high incidence of emergence agitation in human patients, especially in children, increases noradrenaline release in the preoptic area in the rat brain. The clinically observed frequency of emergence agitation with sevoflurane is significantly reduced by drugs activating alpha2 adrenoceptors. The locus coeruleus (LC) is a source nucleus of widely spreading noradrenergic projections in the central nervous system and is also known as one of the principal targets of some alpha2-adrenoceptor agonists, such as dexmedetomidine. The authors analyzed the effects of sevoflurane and other anesthetics on the membrane current of the LC neurons to study the mechanism of the paradoxical "excitatory" effects of the anesthetics. Methods Effects of volatile and nonvolatile anesthetics on the membrane potential and currents of LC neurons in pontine slices of the rat were evaluated. Action potential-dependent transmission was suppressed with tetrodotoxin. Results Sevoflurane at 5% (measured concentration in the recording chamber, 0.5 mm) induced an early-phase inward current in most of LC neurons in a robust manner, which significantly increased the firing frequency in the absence of tetrodotoxin under current clamp recording. Preadministration of dexmedetomidine (1-3 nm) occluded this increase in firing frequency with sevoflurane. This inward current was inhibited by a gap junction inhibitor carbenoxolone and was not observed with nonvolatile general anesthetics and in non-LC neurons examined. Conclusions The excitatory current activated by sevoflurane in LC neurons, likely to be mediated by gap junction-related mechanisms, might be one of the potential cellular mechanisms underlying paradoxical excitatory effect of sevoflurane.