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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044757-02
Application #
2769675
Study Section
Special Emphasis Panel (ZRG4-GRM (01))
Project Start
1997-09-03
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Horvath, Ryan J; Nutile-McMenemy, Nancy; Alkaitis, Matthew S et al. (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557-69
Lacroix-Fralish, Michael L; Tawfik, Vivianne L; Nutile-McMenemy, Nancy et al. (2008) Neuregulin 1 is a pronociceptive cytokine that is regulated by progesterone in the spinal cord: implications for sex specific pain modulation. Eur J Pain 12:94-103
Nutile-McMenemy, Nancy; Elfenbein, Arye; Deleo, Joyce A (2007) Minocycline decreases in vitro microglial motility, beta1-integrin, and Kv1.3 channel expression. J Neurochem 103:2035-46
Lacroix-Fralish, M L; Tawfik, V L; Nutile-McMenemy, N et al. (2006) Progesterone mediates gonadal hormone differences in tactile and thermal hypersensitivity following L5 nerve root ligation in female rats. Neuroscience 138:601-8
Lacroix-Fralish, Michael L; Tawfik, Vivianne L; Tanga, Flobert Y et al. (2006) Differential spinal cord gene expression in rodent models of radicular and neuropathic pain. Anesthesiology 104:1283-92
Sweitzer, S M; Pahl, J L; DeLeo, J A (2006) Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat. Neurosci Lett 400:258-61
Ozaktay, A Cuneyt; Kallakuri, Srinivasu; Takebayashi, Tsuneo et al. (2006) Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats. Eur Spine J 15:1529-37
LaCroix-Fralish, Michael L; Tawfik, Vivianne L; Spratt, Kevin F et al. (2006) Sex differences in lumbar spinal cord gene expression following experimental lumbar radiculopathy. J Mol Neurosci 30:283-95
LaCroix-Fralish, Michael L; Rutkowski, Maria D; Weinstein, James N et al. (2005) The magnitude of mechanical allodynia in a rodent model of lumbar radiculopathy is dependent on strain and sex. Spine (Phila Pa 1976) 30:1821-7
Tawfik, V L; LaCroix-Fralish, M L; Nutile-McMenemy, N et al. (2005) Transcriptional and translational regulation of glial activation by morphine in a rodent model of neuropathic pain. J Pharmacol Exp Ther 313:1239-47

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