Cell Cycle Pathway Inhibition Decreases Peripheral Neuropathic Pain

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DESCRIPTION (provided by applicant): Neuropathic pain affects over 3% of the U.S. population. It is described as being severe, persistent and highly resistant to conventional treatment. As such, neuropathic pain results in life-long suffering and decreased quality of life for these patients. The mechanisms underlying the development and persistence of neuropathic pain remain unclear; however, there are several factors that could contribute to its development, including astroglial and microglial activation in the spinal dorsal horn (SDH) and activation of satellite glial cells in the dorsal root ganglia (DRG). All of these factors can contribute to increased hyperexcitability of DRG and SDH neurons, which increases pain transmission. Following nerve injury in the central nervous system, cell cycle pathways are activated that lead to astroglial proliferation and microglial activation with inflammation. This response to cell cycl activation may contribute to the development of central neuropathic pain. The purpose of this study is to examine the role of the cell cycle in peripheral neuropathic pain and test our hypothesis that inhibiting the cell cycle pathway decreases neuronal hyperexcitability and mechanical allodynia after peripheral nerve injury, likely by reducing astrogliosis in the spinal cord and satellite glial cell activation in the DRG. Using nocifensive behavioral testing, electrophysiological recording, Western blot and immunohistochemical analyses in a mouse model of peripheral nerve injury (partial sciatic nerve ligation), we will test our hypothesis with the following Specific Aims. Specific Aim 1: To demonstrate that the cell cycle pathway is activated in the spinal dorsal horn (SDH) and dorsal root ganglia (DRG) in a mouse model of peripheral nerve injury. Specific Aim 2: To demonstrate that inhibiting cell cycle activation in th SDH and DRG decreases allodynia and neuronal hyperexcitability after peripheral nerve injury. The results of this study will be highly important and quickly translatable from the preclinical to the clinical setting, since several cell cycle inhibitor drugs are already in clinical trials for cncer treatment. The findings from this study will also have a broad impact and increase our mechanistic knowledge across chronic pain states.