Sevoflurane modulates both GABAA and GABAB receptors in area CA1 of rat hippocampus

Abstract

It has been suggested that volatile anaesthetics enhance synaptic inhibition via gamma-aminobutyric acid (GABA) in the central nervous system. We have examined the effects of sevoflurane on GABAA and GABAB receptors in rat hippocampus in vitro. Extracellular recordings were used to record field potentials in rat CA1 pyramidal neurones of transverse hippocampal slices, stimulated electrically via stratum radiatum input. Sevoflurane 0.4-5.0 vol% decreased the amplitudes of population spikes (PS) of CA1 neurones in a concentration-dependent (calculated ED50 = 6.31 vol%) and reversible manner. The GABAA antagonist, bicuculline methiodide 5 x 10(-5) mol litre-1, induced oscillations (multiple spikes) and blocked the inhibitory actions of sevoflurane in the initial component (up to 24.8 ms) of the oscillation. The latter portion of the oscillation (greater than 24.8 ms) was depressed by sevoflurane. The GABAB antagonist, phaclofen 5 x 10(-4) mol litre-1 partially blocked the effects of sevoflurane on the latter portion of the bicuculline-induced oscillation. Sevoflurane 2.0 vol% significantly enhanced paired-pulse (PS2/PS1) facilitation (from 128.4% to 155.5% at an inter-stimulus interval of 37.9 ms); this enhancement was blocked by phaclofen. Stimulus-response relationships revealed that 2.0 vol% sevoflurane increased the intensity of threshold for PS generation to 109.8% of control. Both the GABAA agonist, muscimol 2 x 10(-5) mol litre-1 and the GABAB agonist, (+/-)-baclofen 10(-5) mol litre-1, potentiated the effects of sevoflurane. Sevoflurane enhanced thresholds by 137.1% and 138.5% of control in the presence of muscimol and (+/-)-baclofen, respectively. The results demonstrate that sevoflurane at clinical concentrations activated both GABAA- and GABAB-mediated inhibitions in area CA1 of the hippocampus, and that sevoflurane and GABA agonists (muscimol and baclofen) acted on different domains on the GABAA and GABAB receptors, respectively.

Flumazenil expedites recovery from sevoflurane/remifentanil anaesthesia when administered to healthy unpremedicated patients

“…15 Volatile anaesthetics enhance synaptic inhibition through GABA in the central nervous system (CNS). [16][17][18][19] The precise mechanism by which sevoflurane produces loss of consciousness is unknown. It has been demonstrated that sevoflurane and GABA agonists (muscimol, baclofen) act on different domains of the GABA receptor complex.…”

“…It has been demonstrated that sevoflurane and GABA agonists (muscimol, baclofen) act on different domains of the GABA receptor complex. 16,17 It has also been demonstrated that sevoflurane activates at least two distinct domains of the GABA-A receptor, increasing the GABA-ergic transmission by enhancing the affinity of GABA for the GABA receptor and inducing a picrotoxin-mediated antagonism of the GABA-A receptor. 16,17 In the present study, the analeptic role of flumazenil when administered at the end of the surgical procedure was our main interest.…”

Involvement of GABA and opioid peptide receptors in sevoflurane-induced antinociception in rat spinal cord

“…This reversal effect by bicuculline seems unlikely to be involved in a release of a GABA-mediated tonic inhibition, given that 0.1 mg/kg bicuculline in the absence of sevoflurane did not increase nociceptive C responses significantly. Previous studies have revealed that the sevoflurane-induced inhibition of field potentials evoked from CA1 of the hippocampus is partially antagonized by phaclofen, a competitive antagonist of the GABA B receptor [16] . However, the antinocifensive effect of halothane was not affected by the intrathecal administration of GABA B receptor antagonist CGP 35348 [7] .…”

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

“…Hippocampal slices were prepared as previously described [26] . Briefly, brain was rapidly removed, and hippocampus was dissected and sliced transversely to its longitudinal axis (400 µm thick) in cold artificial cerebrospinal fluid (ACSF) with a Rotorslicer DTY-7700 (DSK, Osaka, Japan).…”

“…By phosphorylating specific serine and threonine residues in cellular targets, they affect gene expression, mitosis, cytokinesis, metabolism, and cell death. Many studies demonstrate that modulations of extracellular signal-regulated protein kinases (MEK-ERK1/2, ERK1/2 MAPK) and p38 MAPK activities either by ischemia or by pharmacological agents are important in the genesis of the cytoprotective phenotype [22][23][24][25][26] . To date, no data are available with respect to the role of MAPKs in APC.…”