Investigating the roles of the gliovasculature and neuroinflammation on secondary pain in peripheral inflammation
Rheumatoid Arthritis (RA) is an autoimmune disease that results in inflammation, damage, pain and stiffness in joints. Patients with RA often complain of pain despite inflammation being well managed, or pain in areas with no associated inflammation or damage. This is referred to as secondary or refe...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2021
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| Online Access: | https://eprints.nottingham.ac.uk/64270/ |
| _version_ | 1848800109160038400 |
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| author | Durrant, Alexandra Margaret |
| author_facet | Durrant, Alexandra Margaret |
| author_sort | Durrant, Alexandra Margaret |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Rheumatoid Arthritis (RA) is an autoimmune disease that results in inflammation, damage, pain and stiffness in joints. Patients with RA often complain of pain despite inflammation being well managed, or pain in areas with no associated inflammation or damage. This is referred to as secondary or referred pain, and is a hallmark of central sensitisation. As well as neuronal hyperactivity in the dorsal horn of the spinal cord, there is glial activation and neuroinflammation, both of which are thought to contribute to central sensitisation and the resulting chronic pain. Neural endothelial cells are key components of blood-neural barriers, such as the Blood Spinal Cord Barrier (BSCB), and of the Neurovascular Unit (NVU). There is evidence of BSCB disruption in chronic pain conditions like inflammatory arthritis, and there is an emerging role of neural endothelial cells in contributing to central sensitisation and chronic inflammatory pain.
In this thesis, secondary pain was induced through intra-articular Complete Freund’s Adjuvant (CFA), and the gliovascular response and contribution was investigated through histology, knockdown of endothelial cell-specific Vascular Endothelial Growth Factor Receptor (VEGF-R)2, and pharmacological inhibition of VEGF-R2 and/or Tumour Necrosis Factor α (TNFα). Additionally, single cell in vivo electrophysiology was employed to investigate the neural response to TNFα, and in vitro studies investigated Human Brain Microvascular Endothelial Cell (HBMEC) responses to TNFα and Vascular Endothelial Growth Factor (VEGF)-A165a.
Peripheral inflammation induced robust secondary pain, which was neither prevented or reversed with VEGF-R2 or TNFα inhibition. However, a combination of both VEGF-R2 and TNFα inhibition partially reversed established secondary pain. Peripheral inflammation also led to astrocyte activation in the dorsal horn of the spinal cord. Endothelial-specific VEGF-R2 knockout prevented secondary pain development and associated gliovascular alterations (Beazley-Long et al. 2018b). Using analysis techniques developed in this thesis, astrocyte activation was found to be specific to the spinal dorsal horn vasculature. Additionally, TNFα caused an increase in expression of adhesion molecules by and Human Monocyte-like Cells (THP-1) binding to HBMECs. Exogenous intrathecal TNFα had no impact on spinal dorsal horn neuronal signalling, which was attributed to technical issues.
In conclusion these results indicate the gliovasculature, in particular astrocytes and endothelial cells, undergoes activation in chronic inflammatory pain and central sensitisation. They also support the hypothesis that endothelial cells are involved in maintaining chronic pain through their activation by inflammatory mediators and subsequent downstream signalling on glial cells and neurones. |
| first_indexed | 2025-11-14T20:46:20Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-64270 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:46:20Z |
| publishDate | 2021 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-642702025-02-28T15:09:36Z https://eprints.nottingham.ac.uk/64270/ Investigating the roles of the gliovasculature and neuroinflammation on secondary pain in peripheral inflammation Durrant, Alexandra Margaret Rheumatoid Arthritis (RA) is an autoimmune disease that results in inflammation, damage, pain and stiffness in joints. Patients with RA often complain of pain despite inflammation being well managed, or pain in areas with no associated inflammation or damage. This is referred to as secondary or referred pain, and is a hallmark of central sensitisation. As well as neuronal hyperactivity in the dorsal horn of the spinal cord, there is glial activation and neuroinflammation, both of which are thought to contribute to central sensitisation and the resulting chronic pain. Neural endothelial cells are key components of blood-neural barriers, such as the Blood Spinal Cord Barrier (BSCB), and of the Neurovascular Unit (NVU). There is evidence of BSCB disruption in chronic pain conditions like inflammatory arthritis, and there is an emerging role of neural endothelial cells in contributing to central sensitisation and chronic inflammatory pain. In this thesis, secondary pain was induced through intra-articular Complete Freund’s Adjuvant (CFA), and the gliovascular response and contribution was investigated through histology, knockdown of endothelial cell-specific Vascular Endothelial Growth Factor Receptor (VEGF-R)2, and pharmacological inhibition of VEGF-R2 and/or Tumour Necrosis Factor α (TNFα). Additionally, single cell in vivo electrophysiology was employed to investigate the neural response to TNFα, and in vitro studies investigated Human Brain Microvascular Endothelial Cell (HBMEC) responses to TNFα and Vascular Endothelial Growth Factor (VEGF)-A165a. Peripheral inflammation induced robust secondary pain, which was neither prevented or reversed with VEGF-R2 or TNFα inhibition. However, a combination of both VEGF-R2 and TNFα inhibition partially reversed established secondary pain. Peripheral inflammation also led to astrocyte activation in the dorsal horn of the spinal cord. Endothelial-specific VEGF-R2 knockout prevented secondary pain development and associated gliovascular alterations (Beazley-Long et al. 2018b). Using analysis techniques developed in this thesis, astrocyte activation was found to be specific to the spinal dorsal horn vasculature. Additionally, TNFα caused an increase in expression of adhesion molecules by and Human Monocyte-like Cells (THP-1) binding to HBMECs. Exogenous intrathecal TNFα had no impact on spinal dorsal horn neuronal signalling, which was attributed to technical issues. In conclusion these results indicate the gliovasculature, in particular astrocytes and endothelial cells, undergoes activation in chronic inflammatory pain and central sensitisation. They also support the hypothesis that endothelial cells are involved in maintaining chronic pain through their activation by inflammatory mediators and subsequent downstream signalling on glial cells and neurones. 2021-08-04 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/64270/1/Durrant-A_Thesis-Corrected%2BSigned.pdf Durrant, Alexandra Margaret (2021) Investigating the roles of the gliovasculature and neuroinflammation on secondary pain in peripheral inflammation. PhD thesis, University of Nottingham. Gliovasculature Neuroinflammation Secondary pain Peripheral inflammation |
| spellingShingle | Gliovasculature Neuroinflammation Secondary pain Peripheral inflammation Durrant, Alexandra Margaret Investigating the roles of the gliovasculature and neuroinflammation on secondary pain in peripheral inflammation |
| title | Investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| title_full | Investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| title_fullStr | Investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| title_full_unstemmed | Investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| title_short | Investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| title_sort | investigating the roles of the gliovasculature and
neuroinflammation on secondary pain in peripheral inflammation |
| topic | Gliovasculature Neuroinflammation Secondary pain Peripheral inflammation |
| url | https://eprints.nottingham.ac.uk/64270/ |