Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.747761
Title: An investigation of the pharmacological modulation of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis
Author: Lockwood, S. M.
ISNI:       0000 0004 7232 4928
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
Osteoarthritis (OA) is a disabling disease of the synovial joints. Structurally, OA involves the degenerative breakdown of articular cartilage, inflammation of the synovium and sclerosis of the subchondral bone, which ultimately results in a loss of function and integrity of the synovial joints. Clinically, it is the chronic pain associated with OA that causes patients to seek medical attention. Traditional analgesics used to relieve the chronic pain associated with OA aim to alleviate peripheral nociception at the level of the diseased joint. However, OA patients often develop referred pain and suffer with chronic pain even after total joint replacement surgery, which indicates that the chronic pain associated with OA is not always driven by purely peripheral mechanisms. Therefore, a better understanding of the central mechanisms involved in the development of OA associated chronic pain may aid the development of effective analgesics that tackle the centrally driven element. Diffuse Noxious Inhibitory Controls (DNIC) describes the phenomenon where one pain inhibits another; this system utilizes endogenous descending inhibitory controls, which mediate an inhibitory effect at the level of the spinal cord. In order to characterize this system in rats, in vivo electrophysiological recordings were made from single unit dorsal horn convergent neurons. The dorsal horn neurons were activated by mechanical and thermal stimulation of the hind paw and DNIC was induced by a concurrent noxious conditioning pinch. This thesis aimed to investigate the pharmacology of DNIC. OA of the knee was modeled in this thesis with a 2mg monoiodoacetate (MIA) intrarticular injection in the rat. This thesis investigated central neuronal plasticity with spinal electrophysiology, assessed the functionality of descending controls through measuring DNIC responses, and characterized the joint histopathology and pain-like behaviour associated with this model. Studies presented in this thesis confirmed that DNIC are mediated via noradrenergic inhibitory descending controls, but that serotonergic descending controls can also influence the expression of DNIC. Early phase MIA animals (2-6 days post injection) displayed significant mechanical hypersensitivity, yet showed little articular cartilage degradation and had a functional DNIC system. DNIC expression was abolished in early phase animals through blocking the actions of spinal α2-adrenoceptors with the antagonist atipamezole, while blocking the actions of spinal 5-HT7 receptors reduced DNIC expression. Late phase MIA animals (14-20 days post injection) demonstrated significant articular cartilage degradation, mechanical hypersensitivity, and an abolished DNIC system. DNIC expression was restored in late phase MIA animals by enhancing noradrenergic modulation with the NRI and μ-opioid receptor agonist tapentadol, and by activating spinal 5-HT7 receptors with the selective 5-HT7 receptor agonist AS-19. In addition, pregbalin significantly reduced spinal neuronal responses in late phase MIA animals yet had no effect in early phase animals. Overall, these results suggest there is a decreased noradrenergic inhibitory descending drive acting at spinal α2-adrenoceptors, and modulation of serotonergic descending controls acting at spinal 5-HT7 receptors in late phase MIA animals. The studies presented in this thesis demonstrate the applications of assessing DNIC in this experimental model of OA, that the DNIC system becomes abolished as the model progresses, and that DNIC can be restored through pharmacologically manipulating monoaminergic descending controls. Overall, this may represent a strategy for relieving centrally driven OA associated chronic pain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.747761  DOI: Not available
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