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Pain-related behavior is associated with increased joint innervation, ipsilateral dorsal horn gliosis, and dorsal root ganglia activating transcription factor 3 expression in a rat ankle joint model of osteoarthritis

Innervation Model

Goal of the Study?

In this study 1, the authors use a rat model to examine the time-course development of pathological joint changes and correlate them with pain-related behaviour in OA. 

Why are they doing this study?

There is a very high incidence of Osteoarthritis (OA) in the elderly population, and it is a leading cause of disability and pain. However, there is a lack of knowledge of OA’s pain mechanisms, particularly the role that neuropathic pain (NP) plays in OA.

OA has been described as a degenerative rather than an inflammatory disease. However, in recent years research has identified the many inflammatory processes that take place in OA.  Existing OA models have shown how this inflammation is supported by overexpression of nerve growth factors causing nociceptive fibres to grow into inflamed joints. This inflammatory process helps explain why there is a poor correlation between radiographic changes and pain levels in OA patients. Moreover, some patients continue to experience pain after a total joint replacement, suggesting that OA can result in neuropathic pain (NP). 

What was done?

The researchers used a rat monoiodoacetate (MIA) model of the ankle joint. MIA results in pathological changes and pain-like behaviour common with those observed in human OA. This model has been used extensively in research and is well validated.

They injected MIA or saline into a total of 126 male rats. For this study, they used the rat ankle joint as it receives most of its nerve supply from the sciatic nerve, which is used most commonly in NP models. From this, they assessed a variety of changes, including pain-related behaviour, hypersensitivity, reaction to cold and heat, changes to normal movement, cartilage degeneration, bone degeneration, and the effects of drug treatments.

What did they find?

 Overall, the study provided a time-course view of the development of pathological changes to the joint and the associated pain-related behaviours. 

The researchers found significant innervation increases at specific periods of time that coincided with mechanical hypersensitivity at 4 weeks and pain in response to cold at 5 weeks. X-ray findings showed significant cartilage and bone degeneration and joint space narrowing at 5 and 10 weeks. 

The study also illustrated changes in sensory and sympathetic innervation of joints in the subchondral bone and synovial membrane at 5 and 10 weeks.  This increased concentration of sensory and sympathetic fibres was associated with pain-related behaviour and similar to those observed in NP models. Furthermore, they found that pain-related behaviour and extensive joint damage were associated with the expression of activating transcription factor 3 (ATF3) in the dorsal root ganglia (DRG), as well as the microglia and astrocyte changes in the dorsal horn. Using various pharmacological treatments to inhibit or block sympathetic fibres and glial could suppress pain-related behaviour. They argue that these findings suggest that multiple factors contribute to OA pain, including inflammatory changes in the joints, supporting the theory of a neuropathic component in OA.

Why do these findings matter?

As pain is the main reason patients seek medical help, effective pain management is critical to improving life quality. Therefore, understanding what causes pain will help in the development of pain management protocols and treatments. 


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