Modulation of Sensory Transmission by Virally Delivered Genes

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The somatic sensory system carries information on touch, temperature and pain to the brain. Nerve cells innervating the skin called 'first-order' neurons send signals to the spinal cord segments, where they make functional connections called synapses to neurons that carry information up and down the spinal column. Biochemical compounds called neurotransmitters are released by the first-order cells to activate or inhibit these target 'second- order' cells, and an important class of these signaling molecules is known as peptides. This project addresses the role of the peptides enkephalin, neuropeptide Y (NPY), and calcitonin-gene related peptide (CGRP) in this neurotransmission. Particular genes or anti-sense constructs will be delivered by a novel methodology utilizing modified viruses, to increase or decrease the production of these peptides in the first-order sensory neurons. Molecular analysis of gene expression, a behavioral assay for sensation, and pharmacological manipulation will determine how the peptides act, and what receptor molecules on the cell surface membranes are responsible for their action. Results are expected to clarify how enkephalins and NPY inhibit sensory transmission, while CGRP facilitates it. This project will have impact beyond simply somatosensory transmission, because it will clarify mechanisms of action for particular neurotransmitters used in other parts of the brain, and the gene-delivery methods to be perfected here will provide a powerful tool to study the roles of other molecular components in neuronal function.