Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/117957
Type: Thesis
Title: Exploring the Role of Spinal Glia and Toll-Like Receptor 4 in the Development of Endometriosis and Neuroimmune-Associated Pain
Author: Dodds, Kelsi Nicole
Issue Date: 2018
School/Discipline: Adelaide Medical School
Abstract: Endometriosis is an oestrogen-dependent, chronic inflammatory condition in females, characterised by the presence of endometrial-like tissue forming lesions on extra-uterine sites; typically within the pelvis. The most common and debilitating clinical symptom is pain, including dysmenorrhoea, dyspareunia and persistent pelvic pain. However, the severity of reported pain seldom correlates with the extent of endometriosis lesions, and removal of lesions does not always eliminate pain. This disconnection between the peripheral pathology and pain symptoms suggests that central sensitisation processes may occur in women with endometriosis. Accordingly, researchers have thus far investigated neuronal contributions to central sensitisation associated with this condition. However, it is well recognised that adaptations in the reactivity of spinal glial cells (astrocytes and microglia) may also facilitate central sensitisation, by releasing inflammatory mediators that enhance excitatory, and/or reduce inhibitory, neuronal signalling (‘neuroimmune communication’). Whether these glial-mediated inflammatory processes contribute to central sensitisation in the context of endometriosis remains to be established. Therefore, the initial aims of this thesis were to develop and optimise a minimally-invasive mouse model of endometriosis (Chapter 3), and to determine whether spinal glial adaptations that may contribute to central sensitisation occur in this model (Chapter 4). Recent studies suggest that inflammatory mediators, released by highly reactive spinal glial cells, may facilitate inflammatory disease processes in the periphery by stimulating neurogenic inflammation. In this case, neuroimmune-mediated central sensitisation may not only contribute to exaggerated pain (peripheral-to-central signalling), but also in sensitising afferent neurons to establish and maintain peripheral inflammatory conditions (central-to-peripheral signalling). Moreover, the central inflammation induced by spinal glia, as well as peripheral inflammation by peritoneal immune cells (such as macrophages), can be activated by stimulation of the innate immune pattern recognition receptor, Toll-like receptor 4 (TLR4). While preliminary studies have suggested that altered TLR4 signalling may contribute to endometriosis, a role for peripheral and central TLR4 activity in the development of lesions and/or the associated pain has yet to be thoroughly investigated. The subsequent aims of this study were therefore to characterise endometriosis-like lesion development and neuroimmune-associated pain by manipulating TLR4 activity both centrally and peripherally (Chapters 5-7). The studies presented herein demonstrate that: mice with endometriosis-like lesions display changes in spinal glial expression, which correlate spatially with the locations of lesions in the periphery; an overall reduction in TLR4 activity promotes lesion development, alters glial-associated inflammatory signalling and attenuates pain behaviour; enhanced central TLR4 activity may stimulate lesion growth; and enhanced peripheral TLR4 activity facilitates lesion establishment, alters glial-associated inflammatory signalling and heightens pain behaviour. Collectively, these results highlight that central neuroimmune pathways, including those stimulated via TLR4, may be involved in endometriosis-related pain and possibly neurogenically-mediated lesion growth. In addition, both a deficiency and an excess in peripheral TLR4 activity can lead to a greater burden of endometriosis lesions. With future research, tailoring treatments to maintain a fine balance of receptor activity in central and peripheral tissues may prove to be a necessary and viable method to limit lesion development and pain symptoms in endometriosis patients.
Advisor: Hutchinson, Mark R.
Beckett, Elizabeth A. H.
Evans, Susan F.
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018
Keywords: Endometriosis
glia
neuroimmune
spinal cord
pain
Toll-like receptor 4
Provenance: This thesis is temporarily unavailable.
Appears in Collections:Research Theses

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