The immobilizing potencies of general anesthetics are determined by the minimum concentration necessary to ablate multisegmental, rhythmic locomotor-type movements elicited by supramaximal noxious stimuli. However, almost no data exist regarding anesthetic action on locomotor systems that mediate this movement. The proposed studies aim to understand how volatile anesthetics (halothane and isoflurane) affect specific classes of movement-generating spinal locomotor and medullary neurons. Projects entail single-unit extracellular electrophysiology in both rat in vivo and lamprey isolated spinal cord preparations, with pharmacological approaches applied to lamprey.
Aim 1 : We will determine if volatile agents direcly disrupt locomotor networks. We hypothesize that anesthetics block responses of spinal locomotor neurons to both supramaximal noxious stimuli and electrical microstimulation of the mesencephalic locomotor region (MLR) at concentrations necessary to block movement. In lamprey, we will identify excitatory and inhibitory central pattern generating (CPG) neurons using spike-triggered averaging and antidromic activation. We hypothesize that anesthetics suppress excitatory CPG neurons more than inhibitory neurons.
Aim 2 : Using pharmacological approaches in lamprey, we will determine if volatile anesthetics act largely by direct suppression of excitatory CPG networks. We hypothesize that GABAA and glycine receptor antagonists do not significantly change anesthetic requirements, and that volatile anesthetics affect the locomotor rhythm consistent with effects on group I metabotropic glutamate receptor antagonists, but not consistent with effects of AMPA and NMDA receptor antagonists.
Aim 3 : In both rat and lamprey preparations, we will determine if volatile agents depress descending locomotor drive to the spinal cord by a supraspinal action. We hypothesize that anesthetics depress responses of rat reticulospinal medullary neurons to noxious stimuli as well as to MLR microstimulation, and that in the lamprey, selective delivery of anesthetics to the brainstem depresses reticulospinal neuronal responses and motor responses to MLR microstimulation. General anesthetics are dangerous, depressing blood pressure, respiration, and thermoregulation at clinical concentrations. Results from these projects will increase our understanding of how and where anesthetics act in the nervous system, contributing to the development of safer anesthetics and clinical practices.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078167-05
Application #
7858193
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2006-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$214,696
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
Inceoglu, Bora; Wagner, Karen; Schebb, Nils H et al. (2011) Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP. Proc Natl Acad Sci U S A 108:5093-7
Jinks, Steven L; Andrada, Jason (2011) Validation and insights of anesthetic action in an early vertebrate network: the isolated lamprey spinal cord. Anesth Analg 113:1033-42
Jinks, Steven L; Andrada, Jason; Satter, Omar (2011) Anesthetic effects on fictive locomotion in the rat isolated spinal cord. Neuroreport 22:655-9
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
Carstens, Earl E; Carstens, Mirela Iodi; Simons, Christopher T et al. (2010) Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats. Neuroreport 21:303-8
Morisseau, Christophe; Inceoglu, Bora; Schmelzer, Kara et al. (2010) Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids. J Lipid Res 51:3481-90
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
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
Jinks, Steven L; Bravo, Milo; Hayes, Shawn G (2008) Volatile anesthetic effects on midbrain-elicited locomotion suggest that the locomotor network in the ventral spinal cord is the primary site for immobility. Anesthesiology 108:1016-24

Showing the most recent 10 out of 16 publications