Peripheral nerve injury results in diminished sensitivity and often, in neuropathic pain. Both constitute a major and currently poorly managed health problem. Nerve-injury induced alterations in sensibility are the result of changes in primary sensory and CNS neurons, which include; 1) the development of abnormal excitability, 2) phenotypic switches altering synaptic transmission, 3) alterations in synaptic connectivity, and 4) cell death. Two mechanisms may contribute to the pathogenesis of the tactile allodynia and hyperalgesia characteristic of neuropathic pain hypersensitivity, 1) a central sensitization of spinal neurons triggered by ongoing nociceptor input, and 2) the sprouting of A-fiber central terminals into areas of the spinal cord normally innervated by nociceptors. Decreased sensitivity reflects failure of peripheral target re-innervation and sensory neuron cell death after peripheral nerve damage. We propose to investigate the pathophysiology of peripheral nerve damage by determining the relative contribution of different mechanisms to the production of the sensory disturbances, with the ultimate aim of developing new treatment strategies. First, we plan to investigate neuropharmacologically and electrophysiologically whether the allodynia produced by nerve injury requires a peripheral drive, by exploiting a spared nerve model to study the extent and contribution of central sensitization following nerve damage. Second, we will use whole cell patch and intracellular recording techniques in an isolated spinal cord preparation to determine whether the altered synaptic connectivity of A-fiber terminals in the dorsal horn contributes to neuropathic allodynia; alone, in combination with, or by producing central sensitization, and how phenotypic changes in damaged sensory neurons relate to these alterations. Third, we will use an explant tissue culture system to examine the signals responsible for inducing the sprouting. Finally, we will exploit stereological techniques to examine cell loss consequent to damage to the peripheral and central axons of primary sensory neurons, and a molecular biological approach (northern blots, in situ hybridization and cell transfection) to investigate the extent to which up-regulation of a cell survival factor, heat shock protein 27, protects cells from cell death after nerve injury in the adult and in neonates.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1 (01))
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Kitt, Cheryl A
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Massachusetts General Hospital
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