The spinal cord is the predominant site where anesthetics act to suppress movement that occurs as the result of noxious stimulation--a fundamental anesthetic goal. Using a systems analysis approach, this proposal will investigate the relationship of anesthetic-induced immobility to (1) wind-up in spinal neurons; (2) the N-methyI-D-aspartate receptor (NMDA-R), the glycine receptor (Gly-R) and the Na+ channel; (3) spinal cord segments that are depressed to result in hindlimb and forelimb immobility.
Aim 1 will test the hypothesis that anesthetics with a predominant or exclusive in vitro action at NMDA receptors will affect wind-up more as compared to those that have moderate or little in vitro actions at the NMDA-R.
This aim will be accomplished by examining the effects of xenon, isoflurane (ISO), halothane (HAL) and propofol on wind-up in lumbar spinal cord neurons in rats, with and without MK-801, an NMDA receptor blocker.
Aims 2 and 3 will test the hypothesis that mice with NMDA-R and Na+ channel mutations which render the mice insensitive to ISO or HAL will have wind-up responses and neuronal responses to thermal stimulation that are likewise less sensitive to ISO and HAL, as compared to wild-type mice. A Gly-R mutant mouse with anesthetic resistance will have anesthetic sensitive wind-up (because Gly-R is not involved in wind-up) but will have anesthetic resistance vis-a-vis thermal noxious stimulation.
Aim 4 will test the hypothesis that isoflurane suppresses forelimb movement resulting from tail or hindlimb stimulation because of action in the cervical spinal cord (presumably at motoneurons), while halothane prevents similar forelimb movement because of action in the lumbosacralcoccygeal cord (presumably at dorsal horn neurons). To accomplish this Aim we will use a vascular bypass preparation that permits differential delivery of either ISO or HAL to the upper and lower torso in rabbits. These proposed studies will further elucidate what spinal cord sites and physiological processes are important to anesthetic-induced immobility.
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