Our research efforts have been directed towards elucidation of anatomic sites of anesthetic action. Our earlier studies indicated that anesthetics such as isoflurane depress the movement response that occurs following noxious stimulation via an action in the spinal cord. In the past grant cycle we determined that isoflurane and propofol action in the spinal cord depressed the ascending transmission of nociceptive impulses to the brain. This resulted in ablation of the noxious-evoked activation of the electroencephalogram (EEG) and single-units in the thalamus and midbrain reticular formation (MRF). Because the MRF and thalamus are critical to consciousness and memory, it is likely that disruption of nociceptive input to these sites decreases the likelihood of consciousness and memory formation during anesthesia. In this proposal we aim to 1) determine whether isoflurane and propofol action at the spinal level affects the """"""""arousal"""""""" state of the brain, as measured by MRF, pedunculopontine tegmental (PPT) and medial thalamic stimulation-induced effects on the EEG; 2) determine the neurotransmitter systems that modulate the ascending transmission of nociceptive impulses to the brain, and how isoflurane and propofol affect these systems. We hypothesize that 1) isoflurane and propofol will increase the threshold stimulation current in the MRF, PPT and medial thalamus required to cause EEG activation; 2) glutamatergic agonists, glycinergic antagonists and GABAergic antagonists applied to the spinal cord will enhance, while glutamatergic antagonists and GABAergic agonists will depress, the ascending transmission of nociceptive impulses to the brain, and thereby cause EEG activation; 3) isoflurane and propofol will indirectly depress evoked glutamate, aspartate and acetylcholine, but enhance GABA concentrations in the cerebral cortex and medial thalamus via an action in the spinal cord. The results of these projects will further our understanding of the in vivo sites where isoflurane and propofol exert their effects. This information will aid the development of newer and safer anesthetics, as well as lead to clinically useful means of modulating the neurotransmitter systems that are themselves modulated by anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057970-06
Application #
6721480
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1998-08-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
6
Fiscal Year
2004
Total Cost
$367,983
Indirect Cost
Name
University of California Davis
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Andrada, Jason; Livingston, Preetha; Lee, Bong Jae et al. (2012) Propofol and etomidate depress cortical, thalamic, and reticular formation neurons during anesthetic-induced unconsciousness. Anesth Analg 114:661-9
Talavera, Jason A; Esser, Steven K; Amzica, Florin et al. (2009) Modeling the GABAergic action of etomidate on the thalamocortical system. Anesth Analg 108:160-7
Judge, Onkar; Hill, Sean; Antognini, Joseph F (2009) Modeling the effects of midazolam on cortical and thalamic neurons. Neurosci Lett 464:135-9
Barter, L S; Antognini, J F (2008) Kinetics and potency of halothane, isoflurane, and desflurane in the Northern Leopard frog Rana pipiens. Vet Res Commun 32:357-65
Antognini, Joseph F; Atherley, Richard J; Laster, Michael J et al. (2007) A method for recording single unit activity in lumbar spinal cord in rats anesthetized with nitrous oxide in a hyperbaric chamber. J Neurosci Methods 160:215-22
Antognini, Joseph F; Raines, Douglas E; Solt, Ken et al. (2007) Hexafluorobenzene acts in the spinal cord, whereas o-difluorobenzene acts in both brain and spinal cord, to produce immobility. Anesth Analg 104:822-8
Antognini, Joseph F; Atherley, Richard J; Dutton, Robert C et al. (2007) The excitatory and inhibitory effects of nitrous oxide on spinal neuronal responses to noxious stimulation. Anesth Analg 104:829-35
Barter, L S; Mark, L O; Smith, A C et al. (2007) Isoflurane potency in the northern leopard frog Rana pipiens is similar to that in mammalian species and is unaffected by decerebration. Vet Res Commun 31:757-63
Merrill, Austin W; Barter, Linda S; Rudolph, Uwe et al. (2006) Propofol's effects on nociceptive behavior and spinal c-fos expression after intraplantar formalin injection in mice with a mutation in the gamma-aminobutyric acid-type(A) receptor beta3 subunit. Anesth Analg 103:478-83, table of contents
Orth, Mashawn; Bravo, Emigdio; Barter, Linda et al. (2006) The differential effects of halothane and isoflurane on electroencephalographic responses to electrical microstimulation of the reticular formation. Anesth Analg 102:1709-14

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