The cellular and molecular basis of general anesthesia has not been satisfactorily defined. Recent evidence points to the spinal cord as the locus of one common anesthetic endpoint, namely absence of movement in response to a painful stimulus.
Specific Aim l of the proposed studies tests the hypothesis that motor neurons participate in the cellular determination of this endpoint,.and probes the molecular basis of anesthetic effects on these cells as it relates to specific voltage-gated and ligand-gated ion channels. Analgesia is another desirable anesthetic endpoint. Anesthetic agents and adjuvants vary in respect to analgesic effect, from potent analgesia through ineffectiveness to hyperalgesia.
Specific Aim 2 tests the hypothesis that spinal actions in addition-to supraspinal effects contribute to these differences. Agents used in anesthesia will be probed to compare their effects on motor output with effects on nociceptive interneurons that project cepahalad in the spinothalamic tract. Inhibition of activity in this tract would contribute both to analgesia and to diminution of arousal in response to painful stimuli. A significant problem in pain management is the hyperalgesia that often follows a tissue injury which produces prolonged noxious stimulation. Changes in synaptic transmission at the spinal level, termed spinal sensitization, are in part responsible. We have discovered and partially characterized two forms of lone term potentiation (LTP) in an in vitro spinal cord preparation which may be related to injury-induced hyperalgesia and a third which may be related to the hyperalgesia observed on abrupt opioid withdrawal.
Specific Aim 3 will characterize these novel forms of LTP, define their mechanisms, and compare their pharmacology to that of animal models of hyperalgesia. The results will increase understanding of this important problem and provide an in vitro model for testing therapeutic strategies. All the proposed studies employ spinal cord isolated from 3 - 12 day old rats. Drugs to be tested include both inhalation and intravenous general anesthetic and hypnotic agents as well as opioid and alpha2 adrenergic analgesics. Methods include extracellular recording of population evoked potentials and single unit responses to stimuli to a peripheral nerve or dorsal root; whole cell ruptured patch electrode recording in current clamp mode from cells identified by physiological characteristics in whole cord; and whole cell ruptured patch voltage clamp of visually identified cells in thin spinal cord slices.
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