Excitatory amino acids (EAAs) likely constitute the most important class of excitatory neurotransmitters in mammalian central nervous system. Their rapid action and ubiquitous presence underlie their pivotal role synaptic communication between neurons at all levels of the neuraxis. The spinal cord is no exception, and primary afferent sensory neurons contain and release glutamate or aspartate in the dorsal horn. The goal of this project is to examine the participation of endogenous EAAs and EAA receptors in the transmission of nociceptive information through the dorsal horn of rats and in synaptic remodeling which may accompany prolonged activation. This project will examine the spinal function of excitatory amino acids (EAAs) and, to a lesser extent substance P (SP), in the transmission of nociceptive signals, and will elucidate antinociceptive mechanisms and assign cellular sites of action to opioid, serotonergic and GABAergic agonists in the spinal cord. We will test several hypotheses concerning the juxtaposition of receptors for these neurotransmitters on common neurons and/or synaptic elements. In addition, we will examine their involvement in development of long term changes in spinal circuitry following chronic changes in afferent input. In conjunction with the first aim above, the experiments will test the participation of EAAs in the relay of information from primary afferent sensory fibers secondary neurons in the spinal cord dorsal horn and of the effects of GABA, opioids, serotonin and cocaine on that transmission. In conjunction with the second aim above, the experiments will evaluate the participation of EAAs in transsynaptic activation of the c-fos protooncogene and in induction of synaptic and neuronal alterations after prolonged activation. The experiments will be carried out at several levels from whole animal electrophysiology, to spinal cord slice intracellular recording, to dissociated neuron recording, to expression of neurotransmitter receptors in oocytes. The results will significantly improve our understanding of spinal nociceptive transmission and analgesic mechanisms, and of spinal mechanisms of adaptation to prolonged stimulation. Understanding analgesic mechanisms at this level of resolution is crucial to the design of new manipulations with enhanced analgesic efficacy and reduced abuse liability.
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