: This proposal requests support for a third five-year cycle for the Program Project Grant (PPG), Sites and Mechanisms of Inhaled Anesthetic Actions. Work of previous cycles revealed that glycine and NMDA receptors may mediate the capacity of inhaled anesthetics to suppress movement in response to noxious stimulation, and that several plausible mediator candidates (5-HT3, GABAA, alpha- 2 adrenergic, AMPA, and kainate receptors, and many potassium channels) probably are not relevant to this effect. The proposed cycle continues this exploration of the basis for immobility, and adds a systems analysis approach to dissect the contribution of spinal cord components, employing neurophysiological techniques and differential perfusion to isolate relevant sites and receptors. The proposed cycle expands efforts to understand another primary inhaled anesthetic effect, the production of amnesia. As with previous cycles, the present PPG proposal applies selective agonists and antagoists in vivo, in hippocampal preparations, and in isolated receptors to determine the relevance and non-relevance of specific ligand- and voltage-gated channels. Finally, the proposed cycle adds a powerful tool, the construction of genetically engineered animals with mutant receptors that respond normally to their ligands (or to transmembrane potential changes) but (in contrast to wild-type animals) are not affected by one or more inhaled anesthetics. Such animals allow a key test of receptor relevance and non-relevance. An example is the proposed SHLA mouse, an animal having an alpha-1 GABAA receptor that responds normally to GABA but is not enhanced by the presence of isoflurane. The test of non-relevance is of particular importance because only a few ionophores probably mediate a specific anesthetic effect (immobility or amnesia), and thus the greater problem is the exclusion of other, far more numerous, plausible candidates.
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