Abstract
Ethanol is a general anesthetic agent as defined by abolition of movement in response to noxious stimulation. This anesthetic endpoint is due to spinal anesthetic actions. This study was designed to test the hypothesis that ethanol acts directly on motor neurons to inhibit excitatory synaptic transmission at glutamate receptors. Whole cell recordings were made in visually identified motor neurons in spinal cord slices from 14- to 23-day-old rats. Currents were evoked by stimulating a dorsal root fragment or by brief pulses of glutamate. Ethanol at general anesthetic concentrations (50–200 mM) depressed both responses. Ethanol also depressed glutamate-evoked responses in the presence of tetrodotoxin (300 nM), showing that its actions are postsynaptic. Block of inhibitory γ-aminobutyric acidAand glycine receptors by bicuculline (50 μM) and strychnine (5 μM), respectively, did not significantly reduce the effects of ethanol on glutamate currents. Ethanol also depressed glutamate-evoked currents when the inhibitory receptors were blocked and eitherd,l-2-amino-5-phosphonopentanoic acid (40 μM) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (10 μM) were applied to block N-methyl-d-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors, respectively. The results show that ethanol exerts direct depressant effects on both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid andN-methyl-d-aspartate glutamate currents in motor neurons. Enhancement of γ-aminobutyric acidA and glycine inhibition is not required for this effect. Direct depression of glutamatergic excitatory transmission by a postsynaptic action on motor neurons thus may contribute to general anesthesia as defined by immobility in response to a noxious stimulus.
Footnotes
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Send reprint requests to: Joan J. Kendig, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305-5117. E-mail: kendig{at}leland.stanford.edu
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↵1 This work was supported by National Institutes of Health Grants NS13108 and GM47818 (to J.J.K.) and a People’s Republic of China State Education Commission Fellowship (to M.Y.W.).
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↵2 Present address: Department of Physiology, Wannan Medical College, Wuhu 241001, People’s Republic of China.
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↵3 Present address: Department of Anesthesia, University of California San Francisco, San Francisco, CA 94143.
- Abbreviations:
- MAC
- minimum alveolar anesthetic concentration
- EPSP
- excitatory postsynaptic potential
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- NMDA
- N-methyl-d-aspartate
- ACSF
- artificial cerebrospinal fluid
- EPSP
- excitatory postsynaptic potential
- EPSC
- excitatory postsynaptic current
- TTX
- tetrodotoxin
- CNQX
- 6-cyano-7-nitroquinoxaline-2,3-dione disodium
- AP-5
- d,l-2-amino-5-phosphonopentanoic acid
- GABA
- γ-aminobutyric acid
- Received September 1, 1998.
- Accepted March 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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