The parent grant is devoted to studying the mechanisms responsible for peripheral neuropathic pain. Peripheral axonal injury changes the expression of hundreds of genes in dorsal root ganglion neurons, including many that contribute to neuropathic pain, by increasing the excitability of the injured neurons and by altering their synaptic transmission and connectivity in the dorsal horn of the spinal cord. In the parent grant, we are studying the regulation of """"""""pain-contributing"""""""" genes and their orchestration by induction of master regulator transcription factors. For the competitive revision we now wish to pursue two completely new questions: Does pain alter sleep architecture, and does sleep deprivation alter pain sensitivity and chronicity? Our overall hypothesis is that the neural plasticity intrinsic to pain and sleep converge, and in consequence the two phenomena are not independent. We predict that pain will alter sleep and that sleep deprivation will alter pain, and we plan pilot experiments to test this. Furthermore, we predict that the changes in sleep produced by pain may alter the transition of acute to chronic pain by generating maladaptive plasticity in the brain.
Peripheral nerve injury can result in severe intractable pain, resistant to most forms of therapy (peripheral neuropathic pain). The studies in the parent grant are designed to determine how changes in gene expression in sensory neurons after nerve damage are orchestrated and act to produce long-term changes in the function and structure of the nervous system. For the competitive revision we will collaborate with Dr Tom Scammell, a world expert on sleep, to explore in mouse models if chronic inflammatory and neuropathic pain alters sleep, and the reverse to determine if sleep deprivation alters acute pain sensitivity and the severity and chronicity of inflammatory and neuropathic pain.
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|Nie, Duyu; Chen, Zehua; Ebrahimi-Fakhari, Darius et al. (2015) The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex. J Neurosci 35:10762-72|
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