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Title: Dissecting the complex roles of peripheral sensory afferent input and supra-spinal influences to pain associated with osteoarthritis
Author: Haywood, Adrian Richard
ISNI:       0000 0004 6351 9766
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2016
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Osteoarthritis is the most common form of arthritis and an increasingly significant clinical problem. It is characterised by varying degrees of chronic pain and joint pathology. However, the structural changes to the joint do not always correlate with the severity of pain experienced. Furthermore, a significant number of patients still experience chronic pain even after joint replacement indicating sensitisation in people with OA. The aim of this thesis was to determine the contribution of peripheral and central mechanisms to the initiation versus the maintenance of pain, in an animal model of OA pain. Two models of OA pain were characterised. Both the MIA and MNX model demonstrated significant pain behaviour, joint pathology and increases in activated microglia and reactive astrocytosis in the spinal cord indicative of sensitisation consistent with human OA. Spinal excitability was further assessed in the MIA model and demonstrated significant increases in evoked EMG responses at late but not early timepoints of the model, suggesting a time- dependent sensitisation. Sensory-specific block of TRPVl-positive joint afferents following intra-articular QX-314 concomitant with capsaicin revealed a significant contribution of afferent input to pain at 7 and 14 days but not at 28 days post-MIA. A descending contribution from the RVM to OA pain was investigated in the MIA model at 14 and 28 days. It was shown that intra-RVM administration of a high dose of p-opioid agonist DAMGO significantly attenuated evoked EMG responses. However a low dose of DAMGO attenuated EMG responses only at 28 days post-MIA and not at 14 days post-MIA suggesting an increased sensitivity of the RVM to the effects of DAMGO. Potential alterations in p-opioid receptor G protein-coupled binding were investigated as a potential mechanism driving the enhanced opioid effect observed. Agonist-stimulated GTPyS-binding autoradiography in RVM slices demonstrated a significant increase in GTPyS binding in MIA-treated rats at 28 days but not at 14 days, compared to saline-treated rats. This thesis provides new insights into the mechanisms driving pain behaviour in the MIA model at different timepoints and suggests a switch from a predominantly peripherally mediated pain at an early stage of the model, to a centrally mediated maintenance of chronic pain. These findings may also inform the development of more effective treatment strategies in patients with OA.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available