There is considerable evidence that in many pain states, abnormal nociceptor properties are important contributing factors. In particular, increased nociceptor sensitivity, ectopic activity generation, and altered central connectivity are recognized as key changes in animal models of pain. This application tests the hypothesis that altered trophic factor expression in the target tissue during development or in the adult induces these changes. Transgenic models will be used that overexpress either NGF or GDNF in the skin. These growth factors support two classes of nociceptors with unique biochemical characteristics that may underlie differences in pain pathways.
The Specific Aims will test the following hypotheses: 1) the level of GDNF expressed in skin regulates the survival of specific types of nociceptive neurons, 2) target-derived NGF and GDNF uniquely regulate the physiological properties of nociceptive neurons and behavioral response to painful stimuli, and 3) skin-derived trophic factors regulate nociceptor differentiation at specific stages of development and cause changes in the adult PNS that lead to hyperalgesia. GDNF and NGF overexpresser transgenic mice and a new inducible model of NGF expression regulated by Cre recombinase expression will be used to examine the dependence of nociceptor neuron development, differentiation, and functional properties on GDNF and NGF produced by the skin. In situ hybridization, immunohistochemistry, behavioral testing, neuronal counting, RT-PCR, and electrophysiology will be used to examine phenotypic and physiologic properties of NGF- and GDNF-dependent nociceptors to determine how they may overlap and differ in chemical phenotype, receptor expression, physiologic properties and peripheral and central projection patterns. The studies proposed here bring a multidisciplinary approach to understanding how NGF and GDNF sculpt the developing sensory system and how they continue to modulate nociceptive function in the adult. Defining the functional properties of these two groups of nociceptors will be important for understanding normal and abnormal nociceptor activity in the adult. By exploring these issues we will be providing answers to basic developmental questions applicable to both the peripheral and central nervous system, as well as providing the foundation for development of therapies for a wide range of disease states in which pain plays a major role.
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