Low back pain is a major clinical problem second only to the common cold in its financial and symptomatic impact on human suffering. The long-term objective is to understand the pathophysiological mechanisms of low back pain with or without associated lumbar radiculopathy. To achieve this goal, we will apply experience with animal models of lumbar radiculopathy and chronic neuropathic pain to evaluate and test the hypothesis. The working hypothesis is that nerve root injury leads to an inflammatory spinal cytokine response that causes the clinical syndrome of low back pain and/or radiculopathy. This hypothesis will be tested in the proposed specific aims: 1) Characterize spinal and dorsal root ganglion (DRG) proinflammatory cytokine (Interleukin (IL)-1b, IL-6 and Tumor Necrosis Factor- a (TNF-a) protein and mRNA in response to nerve root injury in the rat. 2) Evaluate the electrophysiological response when proinflammatory cytokines (IL-1b, IL-6 and TNF-a) are locally applied to lumbar nerve roots in the rat. 3) Compare the effect of general and specific cytokine inhibitors on root injury-related pain behaviors and functional status in rats using epidural, intradural (proximal to the DRG) or epineural (distal to the DRG) routes of drug delivery.
This aim will help direct the clinical question of determining the most effective route of drug delivery for painful lumbar radiculopathy. 4) Determine the synergistic or functional deficits when used in combination with local anesthetic administration. To address these specific aims, the authors propose to use quantitative immunohistochemistry (IHC), and in situ hybridization (ISH), electrophysiology and nociceptive (pain) behavioral assays. The intent is that when completed, the project will provide: Information on the in vivo kinetics of spinal proinflammatory cytokine expression and production in radiculopathy models. Preliminary data to guide and support new pharmacological treatments of acute low back pain. New insight into the relationship between the neuroimmune response of nerve root injury and the clinical phenomenon of low back pain. Preliminary data to direct future studies that evaluate the impact of neuroimmune responses in causation of low back pain with radiculopathy. New information on the pathogenetic distinction between nerve injury central or peripheral to the dorsal root ganglion (a clinically relevant anatomical location). This new knowledge will guide development of novel, non-addictive preventive therapies and treatments for chronic low back pain.
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