Differences in multidimensional phenotype of 2 joint pain models link early weight-bearing deficit to late depressive-like behavior in male mice.

Introduction: Chronic pain is a hallmark of joint diseases. Although these conditions are often accompanied by negative affective symptoms including depression and anxiety, these comorbidities are rarely studied simultaneously in preclinical models where they are poorly characterised. Moreover, how affective symptoms relate to the more obvious sensory and functional symptoms of joint diseases is not well understood. Here, we have addressed these gaps in knowledge. Methods: We used 2 preclinical models of joint pain in male mice and an array of behavioural and molecular assays to fully characterise functional deficits, mechanical hypersensitivity, affective symptoms, and nociceptive signaling in joint pain, as well as investigate their relationship. Results: Ankle joint inflammation and knee osteoarthritis induced mechanical hypersensitivity that lasted at least 3 months and that was not different between the 2 models on most days. However, the models presented with markedly different weight-bearing deficits, molecular profiles, and affective outcomes. Specifically, only the model of knee osteoarthritis was accompanied by an increase in negative affective behaviors, including early changes in circadian patterns, persistent cognitive impairments, and late development of depressive-like behavior. Importantly, the early weight-bearing deficit strongly correlated with the emotional profiles and the hypersensitivity at 3 months, suggesting that early objective functional measures may be used as predictors of long-term affective symptoms and pain. Conclusion: The predictive value of early weight-bearing deficit could prove useful in the clinical setting for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.