Abstract

Recent evidence supports the notion that the spinal cord is the site where anesthetics suppress movement resulting from noxious stimuli. While gains have been made in our understanding of specific neurotransmitter receptors that are modulated by anesthetics, we lack understanding of these anesthetic actions at an ntegrative level, e.g., at which spinal cord locations and types of neurons do anesthetic effects interact to oroduce immobility? To shed light on anesthetic effects on sensorimotor processing, the present proposal will use neurophysiological methods to assess the effects of isoflurane (ISO), halothane (HAL) and propofol (PROP) at several spinal sites (dorsal horn; intermediate and ventral horn) and on anatomically or functionally different neuronal types (wide-dynamic range, nociceptive specific neurons, sensory neurons with ascending projections, pre-motor interneurons).
In Aim 1 we will test the hypothesis that anesthetics differ in their effects on neurons at different depths in the spinal cord. We hypothesize that ISO will have predominant effects at ventral spinal cord sites, whereas HAL and PROP will have effects on both dorsal and ventral spinal cord sites.
In Aim 2 we will test the hypothesis that neurons with ascending projections (such as spinothalamic neurons) are more sensitive to anesthetics as compared to local segmental neurons. Furthermore, in Aim 2, we will test the hypothesis that wide-dynamic range neurons are more resistant to anesthesia compared to nociceptive specific neurons.
In Aim 3, we will test the hypothesis that GABA-A antagonism (picrotoxin), glycine antagonism (strychnine) and glutamate agonism (NMDA) will reverse anesthetic depression of spinal cord neuronal function in an anesthetic-specific way, with GABA antagonism being more specific for PROP and glutamate and glycine antagonism being more specific for ISO and HAL. The results will lead to a better understanding of how anesthetics modulate neuronal function at an integrative systems level. Understanding how and where anesthetics act will eventually lead to the development of better and safer anesthetics, thereby decreasing peri-operative morbidity and mortality and improving public health.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061283-07
Application #
7324777
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2000-04-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
7
Fiscal Year
2008
Total Cost
$185,966
Indirect Cost

  Institution

Name
University of California Davis
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618

  Publications

Jinks, Steven L; Bravo, Milo; Satter, Omar et al. (2010) Brainstem regions affecting minimum alveolar concentration and movement pattern during isoflurane anesthesia. Anesthesiology 112:316-24
Barter, Linda S; Carstens, Earl E; Jinks, Steven L et al. (2009) Rat dorsal horn nociceptive-specific neurons are more sensitive than wide dynamic range neurons to depression by immobilizing doses of volatile anesthetics: an effect partially reversed by the opioid receptor antagonist naloxone. Anesth Analg 109:641-7
Kungys, Gudrun; Kim, Jongbun; Jinks, Steven L et al. (2009) Propofol produces immobility via action in the ventral horn of the spinal cord by a GABAergic mechanism. Anesth Analg 108:1531-7
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
Jinks, Steven L; Carstens, Earl; Antognini, Joseph F (2009) Nitrous oxide-induced analgesia does not influence nitrous oxide's immobilizing requirements. Anesth Analg 109:1111-6
Barter, Linda S; Mark, Laurie O; Antognini, Joseph F (2009) Proprioceptive function is more sensitive than motor function to desflurane anesthesia. Anesth Analg 108:867-72
Barter, Linda S; Mark, Laurie O; Jinks, Steven L et al. (2008) Immobilizing doses of halothane, isoflurane or propofol, do not preferentially depress noxious heat-evoked responses of rat lumbar dorsal horn neurons with ascending projections. Anesth Analg 106:985-90, table of contents
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
Yao, Aubrey; Kim, JongBun; Atherley, Richard et al. (2008) The effects of aromatic anesthetics on dorsal horn neuronal responses to noxious stimulation. Anesth Analg 106:1759-64
Jinks, Steven L; Carstens, Earl E; Antognini, Joseph F (2007) Glutamate receptor blockade in the rostral ventromedial medulla reduces the force of multisegmental motor responses to supramaximal noxious stimuli. Neurosci Lett 426:175-80

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