Development of a mouse model for the study of osteoarthritis pain

Abstract

Murine models of osteoarthritis (OA) provide a potentially powerful tool to elucidate mechanisms responsible for OA pain. However, few studies have examined pain behaviours in relevant OA models in mice. Several models including spontaneous, surgical and chemically induced OA were explored before selecting partial medial meniscectomy of C57BI/6 mice for in-depth study. The development of degenerative joint disease was confirmed using histology which illustrated progressive cartilage damage in a time dependent manner. Pain was assessed by monitoring weight bearing, mechanical hyperalgesia, cold allodynia, mechanical allodynia and vocalisation in response to knee compression for 12 weeks post-surgery. No significant weight bearing deficits were observed during the course of the study. Significant mechanical allodynia was present in the ipsilateral hind limb from 9 weeks following surgery. Hind limb mechanical hyperalgesia and cold allodynia, and increased vocalisation in response to knee compression developed in the ipsilateral limb in two phases. An early phase of hypersensitivities lasted for up to 3 weeks and was reversed by treatment with an NSAID, diclofenac. Pain then resolved for several weeks followed by a second phase of NSAID-insensitive pain after 6 weeks post-surgery. During this phase, all pain behaviours could be reversed by morphine. In contrast, other analgesic drugs (paracetamol, gabapentin and tramadol) had selective effects on only one or two modalities. Pain fluctuated during the second phase with transient periods of reduced pain. At these times underlying hypersensitivities could be unmasked by administration of naloxone indicating that reduced pain was due to endogenous opioids. The role of specific pain receptors in OA pain were investigated in this model of OA using genetically modified mice, novel analgesics and calcium imaging.
The role of specific pain receptors in OA pain were investigated in this model of OA using genetically modified mice, novel analgesics and calcium imaging. Partial medial meniscectomy has proven to be a useful tool for the investigation of the pathophysiology of OA pain and also for the discovery of potential new therapeutics.

Date of Award	2012
Original language	English
Awarding Institution	King's College London
Supervisor	Stuart Bevan (Supervisor) & Marzia Malcangio (Supervisor)