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Title: Pharmacological, neurochemical and functional characterisation of the MIA model of experimental osteoarthritis
Author: Thakur, M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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More than 10 million adults consult their GP each year with arthritis and related conditions. Significantly, painful osteoarthritis imposes a much more significant limitation on function than non-­‐painful osteoarthritis. This has lead to a focus on therapies that offer symptomatic relief for sufferers of painful osteoarthritis. Many existing analgesics that are able to partially reduce patients’ pain have undesirable adverse effects when given chronically, especially in elderly patients. Hence the need for greater understanding of the mechanisms involved in osteoarthritis pain, to aid the development of more effective, better-­‐tolerated analgesics. The MIA model of experimental osteoarthritis uses a single intraarticular injection of the metabolic inhibitor monoiodoacetate (MIA) to induce a joint degeneration that closely resembles osteoarthritis. In rats, the model is associated with joint pain that refers to the hindpaw. This PhD thesis presents work characterizing functional plasticity in the MIA model using spinal cord electrophysiology, behavioural pharmacology and immunohistochemistry. The role of spinal and peripheral nerve hyperpolarization-­‐activated cyclic nucleotide gated cation (HCN) channels in osteoarthritis pain was assessed using the HCN channel blocker, ZD7288. These experiments and others using the KCNQ potassium channel blocker XE991, demonstrate novel physiological roles for these ion channels in nociception. Electrophysiology experiments show that the novel analgesic tapentadol, a joint opioid receptor agonist/noradrenaline reuptake inhibitor, is able to reduce nociceptive spinal activity in the MIA model. Lastly, a series of experiments evaluate the biochemically, behaviourally and pharmacologically distinct phenotypes of two variants of the MIA model. The data gathered in this thesis illustrate a number of novel features of this experimental model of osteoarthritis pain, and will inform the development of novel analgesics for osteoarthritis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available