This is a first NIH grant proposal by a young investigator written in response to the program announcement PA-96-026, Molecular Pharmacology of Anesthetic Action. Its goal is to elucidate the interactive contributions of the spinal cord and brain to anesthetic efficacy. In preceding studies the PI has provided evidence that the spinal cord is the site at which an inhalation agent produces immobility in response to a noxious stimulus, and that cerebral contributions are less important and may even antagonize the spinal actions. The present proposal extends the study of spinal-cerebral interactions to intravenous anesthetic and analgesic agents as well as volatile agents, including isoflurane, nitrous oxide, thiopental, propofol and morphine. In a goat model in which brain and spinal cord (torso) can be independently perfused, the investigator will carry out studies to (1) determine how anesthetic action in the brain influences nociceptive responses in spinal cord and (2) determine how anesthetic action in the spinal cord affects transmission of nociceptive information to the brain. Methods include recording nociceptive responses of single neurons in lumbar dorsal horn, mid-brain reticular formation and thalamus, and changes in cortical EEG evoked by noxious stimulation. Predictions are made about the direction and magnitude of the effects of different agents applied to brain on spinal cord, of different agents applied to torso on dorsal horn cells, and of different agents applied to torso on transmission of nociceptive stimuli to supraspinal areas. Understanding the brain/spinal cord relationship in anesthetic action will contribute to elucidation of the relationship among critical end-points of anesthesia, will guide further research into anesthetic mechanisms, and will lead to site-specific anesthetics.
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