Pain sensation and emotion induced by aromatase inhibitors: a new mouse model

Aromatase inhibitors (AIs) are crucial for hormone receptor-positive breast cancer patients, enhancing disease-free survival and significantly reducing the risk of distant metastasis and local recurrence. However, AI-induced pain and emotional distress can impair the quality of life and medication adherence, leading to premature discontinuation and increased mortality. In this study, we developed a novel mouse model to investigate these effects. We administered different doses of letrozole to young, artificially menopausal female C57BL/6J mice and assessed pain sensation, emotion-related behaviors, and exercise endurance to identify the optimal AI dose and intervention period. This model was further validated in male and naturally menopausal female mice. Letrozole significantly lowered mechanical pain thresholds in all groups, with the most pronounced pain-related behaviors observed in young, artificially menopausal female mice. Notably, these young female mice also experienced prolonged recovery time postwithdrawal. Aromatase inhibitor-induced anxiety and depressive behaviors were exclusive to young, artificially menopausal female mice and not seen in old naturally menopausal female or young male mice. Serum analysis revealed elevated levels of several proinflammatory cytokines, including interleukin-1β, interferon-γ, tumor necrosis factor-α, and interleukin-6, alongside a reduction in thymocyte counts. Administration of diacerein partially alleviated pain-related behaviors. This model provides a valuable platform for exploring the cellular and molecular mechanisms of AI treatment and evaluating potential therapeutic interventions.