The monosodium iodoacetate-induced model of osteoarthritis pain: Behaviour, pharmacological, immunohistochemical and electrophysiological studies

Osteoarthritis (OA), a chronic degenerative joint disease, will affect an increasing number of individuals as the population ages. It is only recently that pain, the main cause of complaint from patients, has become a source of interest. This thesis investigates a chemical model of knee osteoarthritis pain induced by intra-articular injection of monosodium iodoacetate, an inhibitor of glycolysis. After validating this model and developing new behavioural tests to assess mechanical and cooling hypersensitivity as well as ambulatory-evoked pain, the effects of existing analgesics such as morphine and gabapentin following chronic administration were studied. Both agents decreased pain behaviour but with different time-courses. Using the same techniques as well as hindpaw weight-bearing distribution, the role of inflammation in the model was investigated using clinically available drugs: a glucocorticosteroid, methylprednisolone, a TNF (tumor necrosis factor) alpha antagonist, etanercept, and a COX (cyclo-oxygenase) inhibitor, metacam. Based on the effects of these different drugs, inflammation must play a major role during the early stages of the OA induction rather than during the later pain state. Furthermore, in vivo electrophysiology studies revealed a trend towards higher excitability of deeper wide dynamic range neurones to mechanical stimuli in OA rats. Superficial dorsal horn neurokinin-1 (NK-1) receptor expressing neurones were not found to play a significant role in OA-induced behavioural changes. This indicates differences in central sensitisation and descending modulation from the brainstem, compared to other models. A detailed study of neuronal markers in dorsal root ganglia using immunohistochemistry showed no major neuropathic pain component. Finally, AS006, a novel peripherally selective mu-opioid receptor agonist, was shown to reduce pain behaviour. These behavioural, immunohistochemical and electrophysiological results not only validate the use of this model for the study of osteoarthritis pain but reveal several important underlying mechanisms of nociceptive transmission in this condition