The proposed studies will elucidate temporal characteristics, determine receptor dependencies and characterize mechanisms through which spinally acting analgesic agents induce tolerance. Both behavioral and electrophysiological investigations of spinal pain transmission will be conducted in mice and rats made acutely tolerant to analgesics by single intrathecal injections. In vitro studies of the cellular correlates of tolerance will be conducted in conjunction with the behavioral and in vivo electrophysiological studies and with immunohistochemical studies of receptor localization. The proposed project will examine cellular mechanisms underlying changes in potency and efficacy induced by opioid analgesics given spinally. The experiments will examine the effects on the induction of analgesic tolerance of agents promoting and opposing synaptic plasticity, promoting or inhibiting excitatory transmitter release, mimicking neurotrophins, and inhibiting kineses and protein synthesis. The analgesic agents studied will be selected to act at the following types of spinal analgesic receptors: mu opioid, and delta opioid. The experiments will address questions of analgesic potency and efficacy in experimental systems ranging from whole animals to single cells utilizing both behavioral and electrophysiological methods. The behavioral studies will employ brief, escapable, noxious, thermal or chemical stimuli to determine inhibitory effects of spinally administered analgesics under conditions of homologous and heterologous tolerance. The electrophysiological studies will measure extracellular activity of spinal cord neurons coding pain information during epochs of electrical or natural stimulation in anesthetized rats 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. Most of the studies will induce spinal tolerance using single intrathecal injections of long- and short-acting analgesics alone or combinations of analgesic agents; in addition, systemic injections as well as sustained release preparations of morphine will also be studied, comparing potency and efficacy of agonists between naive and tolerant states. Finally, immunohistochemical localization of excitatory (neurokinin and glutamate) and inhibitory (opioid receptors) in spinal cord will be used to determine changes in localization induced by tolerance. 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 the efficacy of analgesics while minimizing their tolerance-inducing and abuse-related side effects.
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