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The glutamate transporters' role in neuropathic pain and cognitive deficits in an animal model of multiple sclerosis Open Access

Descriptions

Other title
Subject/Keyword
EAE
pain
mulitple sclerosis
glutamate transporters
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Olechowski, Camille J
Supervisor and department
Smith, Peter (Pharmacology)
Kerr, Bradley (Anesthesiology and Pain Medicine)
Examining committee member and department
Pitman, Quentin (Physiology and Pharmacology)
Todd, Kathryn (Psychiatry)
Winship, Ian (Psychiatry)
Department
Centre for Neuroscience
Specialization

Date accepted
2013-08-13T10:02:31Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Multiple Sclerosis (MS) is a chronic disease of the central nervous system characterized by demyelination, inflammation and axonal injury. Chronic pain and cognitive deficits affect a large percentage of MS patients. While a number of animal models are available to study the pathophysiology of MS, studies determining the profile of the above-mentioned symptoms associated with MS in these models are minimal. The purpose of this thesis was to characterize both behavioural and cellular changes in sensory and cognitive processes of the MOG35-55 EAE mouse model of MS. In chapter 2, I characterized the changes in pain sensitivity that arises in a chronic relapsing model of EAE. I found that female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35-55) develop a robust allodynia to both cold and tactile stimuli In chapter 3, work was undertaken to determine the underlying mechanisms that generate neuropathic pain in the MOG35-55 EAE model. Additionally, I was interested in how MOG35-55 EAE mice respond to a persistent noxious stimulus. Mice with EAE showed a significant decrease in elicited pain behaviours in response to subcutaneous injection of formalin. I demonstrated that these effects are mediated by decreased glutamate transporter expression associated with the disease. My experiments in Chapter 4 addressed changes in cognitive ability across different severities of EAE to determine if altered pain sensitivity is also associated with behavioural signs indicative of cognitive impairment in this model. I also used the β-lactam antibiotic ceftriaxone, an agent know to increase glutamate transporter levels in vivo to determine if I could attenuate allodynia and NOR deficits by increasing glutamate transporter activity. Ceftriaxone prevented tactile hypersensitivity and normalized performance in the NOR assay in EAE mice This work validates the use of the mouse MOG35-55 EAE model for studying sensory and cognitive changes in a laboratory setting. Furthermore, the results suggest that the glutamate transporter system may be in ideal target for treatment of these changes in patients suffering from similar sensory and cognitive deficits.
Language
English
DOI
doi:10.7939/R3Q81502J
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Olechowski CJ, et al. (2013) Changes in nociceptive sensitivity and object recognition in experimental autoimmune encephalomyelitis (EAE). Exp. NeurologyOlechowski CJ, et al. (2010) A diminished response to formalin stimulation reveals a role for the glutamate transporters in the altered pain sensitivity of mice with experimental autoimmune encephalomyelitis (EAE). Pain 149(3):565-572.Olechowski CJ, Truong JJ, & Kerr BJ (2009) Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE). Pain 141(1-2):156-164.

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