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|Title:||Advanced preclinical assessment of hyper-nociception|
|School/Discipline:||Adelaide Medical School|
|Abstract:||Neuropathic pain is a major health concern with a significant financial burden on the global society. This complex neuroimmune disorder has a significant reliance on cytokines, including IL-1β, in the pathogenesis of neuropathic pain, due to neuroimmune reactions in spinal cord dorsal horn. Currently, there are methodological challenges for repeated Cerebrospinal fluid (CSF) sampling for cytokines in rodents including the terminality nature of CSF sampling which makes the in vivo longitudinal monitoring of the cytokine challenging. To address these challenges, this PhD thesis focuses on neuropathic pain and a novel method applied to quantify the molecular mediators of the exaggerated nociception and specifically IL-1β in a preclinical model of mechanical allodynia. The introduction of this thesis contains two sections. Firstly, neuropathic pain, the associated neuroimmune mediators and the relevance of cytokine signals is discussed. Of specific focus here is the role of Interleukin-1β (IL-1β) in exaggerated pain states. The challenges of quantifying IL-1β in vivo and the importance this information will have for our understanding of the pathogenesis neuropathic pain is presented. In the second section of the introduction, the need for new technology to enable these key biological measurements, with a focus on novel sensing interface-based techniques is reviewed. Of specific note are the functionalization processes applicable in immobilizing bio-receptors on a surgically (intrathecal)-compatible surface to capture a target molecule. The review will also cover the surgical approaches that will enable researchers to access the intrathecal space in rodents with the purpose of measuring intrathecal molecules. Together, these complementary tools, make the measurements of a hypothetical molecule, in this case IL-1β, possible in the spinal cord. In the third chapter, a method to quantify IL-1β in cerebrospinal fluid based on application of a stainless-steel based biosensor in live animals with high sensitivity is presented. These biosensors are functionalized using poly (ethylene glycol) methacrylate (PEGMA) as the tether molecules to immobilize capture antibody. In the fourth chapter, this method will be employed to have the longitudinal in vivo quantification of intrathecal IL-1β during a peripheral neuropathy, chronic constriction injury (CCI). In this chapter, the correlation between behavioural allodynia during the development and maintenance of nerve injury and the repeated sampling of intrathecal IL-1β over 14 days post injury is presented for the first time. In brief, CCI caused a significant increase in intrathecal IL-1β concentrations from day 0 to day 7 through day 14. In the fifth chapter, the literature on peripheral nerve injury models (sciatic based and spinal nerve based) will be systematically reviewed, and the main categories of biomarkers studied with this model of nerve injury will be presented. The results show that cytokines are the dominant biomarker analysed in the sciatic based neuropathies with IL-1β as the most commonly explored. In addition, the pain models associated with IL-1β analyse will be outlined which show that IL-1β increases in all of the models post injury associated with the exacerbation of pain behaviours. In the last chapter, the thesis is concluded by addressing the key findings of three experimental chapters.|
|Dissertation Note:||Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020|
|Provenance:||This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals|
|Appears in Collections:||Research Theses|
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