Structural and pain modifications in models of osteoarthritis

Background: Despite the extensive research into the pathophysiology of osteoarthritis (OA), pain still represents a significant unmet clinical need. This thesis explores the effects of a tropomyosin related kinase A receptor (TrkA) inhibitor and an anti-nerve growth factor (NGF) antibody as interventions to modify inflammation, structural pathology and pain behaviour in rat models of OA. Methods: Rat models of OA (monosodium iodoacetate - MIA and medial meniscal transection – MNX) were assessed for pain behaviour and pathology. Effect of interventions on pain behaviour (weight bearing asymmetry and paw withdrawal thresholds) and structural pathology (macroscopic and microscopic scoring of articular surfaces) to include inflammation were assessed using inhibitors of the NGF-TrkA pathway. Pain Data were analysed longitudinally using area under the curve or independently with Kruskal Wallis test followed by Dunns post hoc. Other data were analysed with Kruskal Wallis test followed by Dunns post hoc. Results: The MIA and MNX models all exhibited inflammation and pain behaviour. The MIA and MNX models displayed both macroscopic and microscopic pathology. Following preventive or therapeutic treatment with the tropomyosin receptor kinase (Trk) A inhibitor AR786, pain behaviour was inhibited in both MIA and MNX models. Synovitis was attenuated only in the MIA model. Analgesia was sustained for up to 10 days in the MNX model following AR786 treatment discontinuation. Preventive and therapeutic treatment with the anti–NGF monoclonal antibody M911 did not alter changes to cartilage pathology. Conclusions: Manifestation of pain, inflammation and alterations in knee joint structure are characteristic features of OA models. NGF might contribute to OA pain through the NGF-TrkA pathway. This contribution might be as a result of facilitating nociception, and inflammation. Further investigation into the mechanisms by which NGF contributes to OA pain through the TrkA receptor might increase therapeutic potential for OA chronic pain relief