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Dissertation/Thesis Abstract

The role of high mobility group box 1 and toll like receptor 4 in a rodent model of neuropathic pain
by Feldman, Polina, Ph.D., Indiana University, 2013, 259; 3617301
Abstract (Summary)

Neuropathic pain is a serious health problem that greatly impairs quality of life. The International Association for the Study of Pain (IASP) defines neuropathic pain as `pain arising as a direct consequence of a lesion or disease affecting the nervous system'. It is important to note that with neuropathy the chronic pain is not a symptom of injury, but rather the pain is itself a disease process. Novel interactions between the nervous system and elements of the immune system may be key facets to a chronic disease state. One of particular note is the recent finding supporting an interaction between an immune response protein high mobility group box 1 (HMGB1) and Toll like receptor 4 (TLR4). HMGB1 is an endogenous ligand for TLR4 that influences the induction of cytokines in many non-neuronal cells. After tissue damage or injury, HMGB1 may function as a neuromodulatory cytokine and influence the production of pro-nociceptive mediators altering the state of sensory neurons. Very little is known about the HMGB1-TLR4 interaction in sensory neurons and whether chronic changes in endogenous HMGB1 signaling influence the establishment of neuropathic pain. This thesis aims to determine whether a physiologically relevant neuroimmune interaction involving endogenous HMGB1 and TLR4 in the dorsal root ganglia is altered following a tibial nerve injury model of neuropathic pain. I hypothesized that sensitization of sensory neurons following a peripheral nerve injury is dependent on endogenous HMGB1 and TLR4. The studies presented here demonstrate that HMGB1 undergoes subcellular redistribution from the nucleus to the cytoplasm in primary afferent neurons following peripheral nerve injury. Further, the presence of extracellular HMGB1 may directly contribute to peripheral sensitization and injury-induced tactile hyperalgesia. Though thought to be important as a pivotal receptor for HMGB1 activation, neuronal protein expression of TLR4 does not appear to influence the effects of HMGB1-dependent behavioral changes following peripheral nerve injury. Taken together, these findings suggest that extracellular HMGB1 may serve as an important endogenous cytokine that contributes to ongoing pain hypersensitivity in a rodent model of neuropathic pain.

Indexing (document details)
Advisor: Oxford, Gerry S., White, Fletcher A.
Commitee: Jones, Kathryn J., Khanna, Rajesh, Shi, Riyi
School: Indiana University
Department: Medical Neurobiology
School Location: United States -- Indiana
Source: DAI-B 75/08(E), Dissertation Abstracts International
Subjects: Neurosciences
Keywords: Cytokine, Hmgb1, Neuropathic, Pain, Tlr4
Publication Number: 3617301
ISBN: 978-1-303-84610-6
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