"Pain has a profound impact on the quality of life and health-associated costs for all Americans...costing the American public more than $100 billion each year in health care, compensation and litigation"(from NIH Guide New directions in Pain Research). Long-term exposure to painful stimuli can elicit changes in the nervous system that are the cause of chronic pain. These changes can be very difficult to reverse. Chronic pain is debilitating for those individuals it affects, and is refractory to most treatments. The goal of our group is to further determine the cellular mechanisms that mediate the persistent alterations in pain observed following injury, by studying both the peripheral nerve and the spinal cord mechanisms initiated by persistent nociception. This is a complex process involving interactions of supporting tissues, the immune system, the somatic and autonomic nervous systems, and all of the extracellular and intracellular messenger systems. The interaction of so many diverse systems makes understanding this process complex and requires a multi-disciplinary team approach for optimal progress. Using the Program Project Mechanism, we propose to form such a team. Project 1 (PI, Alan Light) will study the mechanisms by which astrocytes and microglia become activated by noxious peripheral inputs and how these cells interact with neurons to mediate long-term behavioral changes in pain responses. Project 2 (PI, Lorne Mendell) will make use of in vitro recording methods to examine the mechanisms by which nerve growth factor sensitizes the responses of nociceptive neurons in rat DRG and to determine how this is modified by inflammation. These studied will also address the specificity of the response of nociceptors to different neurotrophins, the time course of their action and the interaction of neurotrophins with other substances (e.g., serotonin) known to activate or sensitive nociceptive afferents. Project 3 (PI, Gerry Oxford) will study the molecular mechanisms by which growth factors, intracellular modulators, and the newly cloned vanilloid receptor interact to produce sensitization in rat dorsal root ganglion cells.