The proposed studies will identify and characterize common mechanisms through which spinally acting analgesic agents produce analgesia and interact with one another. Behavioral and electrophysiological investigations of spinal pain transmission will be conducted in mice and rats. In vitro studies of the cellular effects of these agents and their combinations will be conducted with behavioral and electrophysiological studies in vivo, with rat spinal cord slices in vitro, and with immunohistochemical techniques. The proposed project will examine cellular mechanisms of changes in potency induced by combinations of analgesic agents and by chronic administration of various agents. The agents studied will be drawn from the following list of spinally active analgesic agents: alpha adrenergic, mu opioid, and delta opioid. These receptor systems are thought to share a common transduction system mediated through inhibitory G proteins, Gi or Go. Activation of these G proteins inhibits neuronal activity subserving pain transmission in the spinal cord dorsal horn. The experiments will address questions of potency and efficacy in experimental systems ranging from whole animal to single cells utilizing behavioral and electrophysiological methods. The behavioral studies will employ brief, escapable, noxious, thermal stimuli to determine inhibitory effects of spinally administered analgesics under conditions of heterologous potentiation. The electrophysiological studies will take advantage of technology added to this laboratory with previous support from NIDA; during epochs of electrical or natural stimulation in anesthetized rats, the electrical activity of spinal cord neurons coding pain information will be recorded extracellularly and the effects of iontophoretically applied analgesic drugs and their combinations determined. In slices of spinal cord tissue, similar neurons will be recorded intracellularly to determine the cellular mechanisms of drug action and interaction. Finally, immunohistochemical localization of alpha 2 and delta opioid receptors in spinal cord and dorsal root ganglia will be used to determine co-localization of these receptors in neurons or lack thereof. The results of these studies will improve our knowledge of mechanisms shared by several drugs of abuse. In addition, multi-drug strategies could be developed based on these studies which would maximize efficacy of analgesics while minimizing their morbidity- and abuse-related side effects.
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