Although anesthetic agents have been indispensable in health care for nearly a century and a half, there is no consensus on their essential actions. In addition, undesirable side effects are common. The compounds synthesized and tested for anesthetic potency in the core project provide an unique means to identify which of the many actions of anesthetic agents are essential and to exclude those which are irrelevant side effects. Anesthetic, transitional and non-anesthetic compounds which deviate from the Meyer-Overton Rule will be compared in respect to their effects in two systems: intact isolated neonatal rat spinal cord and dissociated dorsal root ganglion cells. Dorsal and ventral root population evoked responses in spinal cord are mediated by 3 neurotransmitter receptor subtypes which have been implicated in anesthesia: glutamate non-NMDA, glutamate NMDA and GABA/A. This preparation will be used to test the hypothesis that depression of one or another glutamate receptor and/or enhancement of GABA/A receptor activity is a necessary and sufficient mechanism of anesthetic action. Two alternative hypotheses will also be tested. One is that some anesthetics may act by increasing GABA release; this hypothesis will be tested by measuring spontaneous and evoked GABA release from spinal cord. The other is that anesthesia may be related to inhibition of calcium currents. Patch clamp studies on dissociated dorsal root ganglion cells will examine the extent to which anesthetic potency is correlated with effects on calcium currents. The results will provide a rigorous test of proposed mechanisms of anesthesia, and will be useful in designing optimal anesthetic drugs and drug combinations.
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