This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. : Peripheral nerve injury frequently leads to a variety of debilitating chronic pain states that are thought to reflect heightened excitability of ascending spinal nociceptive pathways. Attempts to identify the mechanisms underlying the pathogenesis of chronic pain are hampered by a general lack of knowledge of the connectivity and synaptic efficacy of nociceptors with known populations of second-order interneurons under any condition. The overall goals of the proposed studies are to increase our understanding of the anatomical and functional connectivity between physiologically identified cutaneous nociceptors and specific subpopulations of local and ascending interneurons in the superficial dorsal horn under normal conditions and in an animal model of neuropathic pain, and the role of inhibitory interactions in shaping these patterns of functional connectivity. These studies are motivated by the PI's recent discovery of a novel class of polymodal nociceptors with large, thickly myelinated (A?) fibers. Unlike most nociceptors, their projections to nocireceptive regions of the dorsal horn appear to be unaffected by nerve injury and thus may constitute the principle substrate underlying various neuropathic pain states. Further, because these afferents in normal animals become active well below pain thresholds, they provide an excellent window for investigations of 1) the physiological mechanisms underlying the regulation of nociceptive throughput to higher centers, 2) how these are altered under neuropathic conditions, and 3) the contribution of inhibitory controls to nociceptive processing and throughput to higher centers under both normal and pathologic conditions. The proposed studies will use a combination of electrophysiological, light and ultrastructural microscopical analyses, and computational modeling to address these objectives through the use of physiologically identified nociceptors and anatomically and physiologically identified subsets of second-order spinal interneurons. Detailed knowledge of the cellular mechanisms underlying the normal balance between excitatory and inhibitory interconnections that regulate neuronal activity levels in the superficial dorsal horn, and how this balance is disrupted in pathological conditions, will be pivotal to the development of future strategies in pain management and the translation of these strategies into effective practice.
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