Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice

Background The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol. Methods The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15). Results Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%). Conclusions The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

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A tonic inhibitory conductance in murine spinal neurons: a novel site for anesthetics?

Canadian Journal of Anesthesia/Journal canadien d anesthésie ◽

10.1007/bf03016961 ◽

2006 ◽

Vol 53 (1) ◽

pp. 26317-26317

Author(s):

David Eng ◽

Robert Bonin ◽

John Macdonald ◽

Beverley Orser

Keyword(s):

Spinal Neurons ◽

Inhibitory Conductance

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Gabapentin Increases a Tonic Inhibitory Conductance in Hippocampal Pyramidal Neurons

Anesthesiology ◽

10.1097/00000542-200608000-00015 ◽

2006 ◽

Vol 105 (2) ◽

pp. 325-333 ◽

Cited By ~ 16

Author(s):

Victor Y. Cheng ◽

Robert P. Bonin ◽

Mary W. Chiu ◽

J Glen Newell ◽

John F. MacDonald ◽

...

Keyword(s):

Gabaa Receptors ◽

Hippocampal Neurons ◽

Gabab Receptors ◽

Gamma Aminobutyric Acid ◽

Western Blots ◽

Inhibitory Postsynaptic Currents ◽

Postsynaptic Currents ◽

Inhibitory Conductance ◽

Tonic Current

Background The mechanisms underlying the therapeutic actions of gabapentin remain poorly understood. The chemical structure and behavioral properties of gabapentin strongly suggest actions on inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA); however, gabapentin does not directly modulate GABAA or GABAB receptors. Two distinct forms of GABAergic inhibition occur in the brain: postsynaptic conductance and a persistent tonic inhibitory conductance primarily generated by extrasynaptic GABAA receptors. The aim of this study was to determine whether gabapentin increased the tonic conductance in hippocampal neurons in vitro. As a positive control, the effects of vigabatrin, which irreversibly inhibits GABA transaminase, were also examined. Methods GABAA receptors in hippocampal neurons from embryonic mice were studied using whole cell patch clamp recordings. Miniature inhibitory postsynaptic currents and the tonic current were recorded from cultured neurons that were treated for 36-48 h with gabapentin, vigabatrin, or gabapentin and vigabatrin. To determine whether gabapentin increased the expression of GABAA receptors, Western blots were stained with antibodies selective for alpha1, alpha2, and alpha5 subunits. Results GABAA receptors were insensitive to the acute application of gabapentin, whereas chronic treatment increased the amplitude of the tonic current threefold (EC50 = 209 microm) but did not influence miniature inhibitory postsynaptic currents. Vigabatrin increased the tonic conductance, and the maximally effective concentration did not occlude the actions of gabapentin, which suggests that these compounds act by different mechanisms. Neither gabapentin nor vigabatrin increased the expression of GABAA receptors in the neurons. Conclusions Gabapentin increases a tonic inhibitory conductance in mammalian neurons. High-affinity GABAA receptors that generate the tonic conductance may detect small increases in the ambient concentration of neurotransmitter caused by gabapentin.

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