Attenuation of gap-junction-mediated signaling facilitated anesthetic effect of sevoflurane in the central nervous system of rats.
Accumulating evidence suggests that reduction of intrinsic excitability or synaptic excitation and/or an enhancement of synaptic inhibition underlie the general anesthetic condition. Besides chemical synapse, neurons could communicate with each other by electrical coupling via gap-junctions. We hypothesized that inhibition of cell-to-cell signaling through gap-junction in the central nervous system (CNS) is involved in the anesthetic mechanism of volatile anesthetics. The minimum alveolar concentration (MAC) of sevoflurane was measured after the intracerebroventricular (ICV) or intrathecal (IT) administration of carbenoxolone (CBX), a gap-junction inhibitor, in vivo. The spontaneous oscillation in membrane currents of locus coeruleus neurons that results from electrical coupling between neurons was also recorded from young rat pontine slices by the patch clamp method, and the effect of sevoflurane on this oscillation was examined in vitro. The ICV administration of CBX (125 and 250 micro g/rat) significantly reduced the MAC of sevoflurane dose-dependently, whereas IT injection failed to inhibit the MAC. Sevoflurane at clinically relevant concentrations (0.1-0.5 mM) suppressed the spontaneous oscillation in membrane current concentration-dependently. These suppressions were significant at 0.5 mM with both amplitude and frequency. We suggest that suppression of gap-junction-mediated signaling in the CNS is involved in the anesthetic-induced immobilization by sevoflurane.


CONCLUSIONS
The intracerebroventricular administration of the gap-junction inhibitor, carbenoxolone, reduced the MAC of sevoflurane, and sevoflurane suppressed the signaling through gap-junctions in the central nervous system. The inhibition of gap-junctions may be one of the mechanisms and the site of action of sevoflurane.
Masaki
Eiji
E
Department of Anesthesiology, Jikei University School of Medicine, Tokyo, Japan. ejmasaki@jikei.ac.jp
Kawamura
Masahito
M
Kato
Fusao
F
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008738:Methyl Ethers / Q000493:pharmacokinetics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011650:Pulmonary Alveoli / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D000077149:Sevoflurane; D002229:Carbenoxolone