The proposed experiments will examine the role of inflammatory responses in the dorsal root ganglion (DRG) in the development and persistence of pathologic pain. Inflammatory responses have been observed in the DRG following various clinical conditions that are often associated with acute or chronic pain: lumbar disc herniation/rupture, mechanical compression, viral infection (e.g., shingles, HIV infection), and peripheral nerve injury. Most studies of inflammation in chronic pain have focused on spinal cord, brain, and peripheral nerve. However, it is not known how prolonged inflammation affects the functional or electrophysiological properties of the primary sensory neurons, how the cytokine profile changes in the DRG following inflammatory irritation, and which cytokines are most important in the initiation and persistence of pathological pain states. We have developed a new rat model of localized inflammation of the DRG. This model shows prolonged pain behaviors, spontaneous activity, and changes in a number of different cytokines that are similar to those induced by mechanical compression. The new model allows us to examine the effects of inflammation per se, in the absence of other types of nerve damage. We hypothesize that altered functional properties of the sensory neurons in the inflamed DRGs and the subsequent pathologic pain can be at least partially accounted for by altered activity of the hyperpolarization-activated current (HCN or IH), resulting from imbalanced cytokine expression within the DRG. Using both the mechanical compression and the DRG inflammation models, we will test our hypothesis via 3 Specific Aims (SA). SA1: Identify significantly altered cytokines/chemokines in the locally inflamed DRGs. SA2. Assess changes in the electrophysiological properties of DRG neurons after direct and prolonged inflammatory irritation, and determine if the IH plays an important role in increased excitability and spontaneous activity. SA3. Manipulate the levels of key cytokines (identified in SA1) in vivo to determine their contribution to pain behaviors and the underlying changes in neuronal electrical properties. Using our previously developed methods for long term in vivo perfusion of DRG, we will study the effects of selected cytokines and cytokine antagonists on the functional properties of DRG neurons including IH activity, and correlate these effects to behavioral measures of hyperalgesia and allodynia. By balancing the cytokine profiles in the DRG, we hope to prevent the development of hyperexcitability of DRG neurons and reduce the pain and hyperalgesia in animal models. Results will provide new insights into the mechanism of intractable pathologic pain, and suggest new therapeutic targets. Chronic pain conditions are common, long-lasting, and debilitating. We propose to study the newly recognized role of inflammation in chronic pain. Using a rat model, we will determine how inflammation directly affects the neurons that sense pain. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS055860-01A2
Application #
7373674
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-12-15
Project End
2012-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
1
Fiscal Year
2008
Total Cost
$336,350
Indirect Cost
Name
University of Cincinnati
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ibrahim, Shaimaa I A; Xie, Wenrui; Strong, Judith A et al. (2018) Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain. Front Cell Neurosci 12:453
Strong, Judith A (2018) High-fat diet and post-operative pain: Why the hospital cafeteria may matter. Brain Behav Immun 74:45-46
Song, Zongbin; Xie, Wenrui; Strong, Judith A et al. (2018) High-fat diet exacerbates postoperative pain and inflammation in a sex-dependent manner. Pain 159:1731-1741
Li, Ai-Ling; Zhang, Jing-Dong; Xie, Wenrui et al. (2018) Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models. Neurosci Bull 34:85-97
Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J et al. (2017) FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Arch 469:195-212
Xie, Wenrui; Strong, Judith A; Zhang, Jun-Ming (2017) Active Nerve Regeneration with Failed Target Reinnervation Drives Persistent Neuropathic Pain. eNeuro 4:
Song, Zongbin; Xie, Wenrui; Chen, Sisi et al. (2017) High-fat diet increases pain behaviors in rats with or without obesity. Sci Rep 7:10350
Chen, S; Xie, W; Strong, J A et al. (2016) Sciatic endometriosis induces mechanical hypersensitivity, segmental nerve damage, and robust local inflammation in rats. Eur J Pain 20:1044-57
Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy et al. (2016) Upregulation of the sodium channel NaV?4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation. Pain 157:879-91
Xie, Wenrui; Chen, Sisi; Strong, Judith A et al. (2016) Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain. J Neurosci 36:8712-25

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