Abstract
IntroductionAnimal models currently used in osteoarthritis-associated pain research inadequately reproduce the initiating events and structural pathology of human osteoarthritis. Conversely, intra-articular injection of collagenase is a structurally relevant model, as it induces articular degeneration both by digesting collagen from cartilage and by causing articular instability, thereby reproducing some of the main events associated with osteoarthritis onset and development. Here, we evaluated if the intra-articular injection of collagenase can be an alternative model to study nociception associated with osteoarthritis.MethodsOsteoarthritis was induced by two intra-articular injections of either 250 U or 500 U of collagenase into the left knee joint of adult male Wistar rats. A six weeks time-course assessment of movement- and loading-induced nociception was performed by the Knee-Bend and CatWalk tests. The effect of morphine, lidocaine and diclofenac on nociceptive behaviour was evaluated in animals injected with 500 U of collagenase. Joint histopathology was scored for both doses throughout time. The expression of transient receptor potential vanilloid 1 (TRPV1) in ipsilateral dorsal root ganglia (DRG) was evaluated.ResultsAn increase in nociceptive behaviour associated with movement and loading of affected joints was observed after intra-articular collagenase injection. With the 500 U dose of collagenase, there was a significant correlation between the behavioural and the histopathological osteoarthritis-like structural changes developed after six weeks. One week after injection of 500 U collagenase, swelling of the injected knee and inflammation of the synovial membrane were also observed, indicating the occurrence of an early inflammatory reaction. Behavioural changes induced by the 500 U dose of collagenase were overall effectively reversed by morphine and lidocaine. Diclofenac was effective one week after injection. TRPV1 expression increased six weeks after 500 U collagenase injection. ConclusionWe conclude that the intra-articular injection of 500 U collagenase in the knee of rats can be an alternative model for the study of nociception associated with osteoarthritis, since it induces significant nociceptive alterations associated with relevant osteoarthritis-like joint structural changes.
Highlights
Animal models currently used in osteoarthritis-associated pain research inadequately reproduce the initiating events and structural pathology of human osteoarthritis
To assess if inflammation occurs during the onset and/or development of the model, we evaluated the effect of the non-steroidal anti-inflammatory drug (NSAID) diclofenac
Joint swelling Signs of inflammation were detected after collagenase injection, denoted by a dose dependent increase in the difference between the ipsilateral and contralateral knee diameter at one week, significant only for the 500 U dose (P
Summary
Animal models currently used in osteoarthritis-associated pain research inadequately reproduce the initiating events and structural pathology of human osteoarthritis. Pain associated with osteoarthritis (OA) affects about 10% of the world’s population over 60 years [1] having, a high individual and socio-economic impact. It is exacerbated both by movement and loading on an affected joint [2], being the predominant reason for patients to seek medical help. A model that comprises both the reproduction of the initiating events and joint tissue pathology observed in human OA as well as the induction of relevant nociceptive responses that mimic patients’ main complaints, such as increased nociception due to movement and loading on the affected joint, would certainly be a clinically-relevant model for the study of OA pain
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