Aromatase inhibitors induce pain-like musculoskeletal symptoms in mice: behavioural, pharmacological and pathophysiological characterization.

Abstract

BACKGROUND AND PURPOSE: Breast cancer, one of the most common cancers in women, primarily manifests as estrogen receptor-positive tumours in post-menopausal women. Aromatase inhibitors (AIs) such as letrozole are the most effective standard adjuvant endocrine therapy. However, the majority of AI-treated patients experience musculoskeletal symptoms (AIMSS), which can lead to premature discontinuation of treatment. Well-characterized animal models are essential to better understand the various mechanisms of AIMSS. EXPERIMENTAL APPROACH: We studied the development of musculoskeletal symptoms in ovariectomized (OVX) female C57BL/6J mice treated chronically with letrozole. We performed evoked and non-evoked behavioural measurements and assessed the extent of estrogen dependence of these changes. Electrophysiological studies and histological analyses of sciatic nerves were performed. Finally, we investigated whether letrozole was associated with the development of hyperexcitability of nociceptive neurons and an increase in pro-inflammatory cytokines in dorsal root ganglia. KEY RESULTS: Increasing doses of letrozole led to the development of musculoskeletal symptoms in evoked and non-evoked pain-like behavioural tests. These symptoms appear to be largely mediated by the decrease in estrogen levels. In addition, duloxetine reversed many of these behavioural changes. These symptoms were associated with a reduction in compound muscle action potentials and a decrease in sensory nerve conduction with loss of small amyelinated fibres. Furthermore, an increase in the excitability of nociceptor neurons associated with inflammation in the DRGs was induced by letrozole. CONCLUSION AND IMPLICATIONS: We characterized a relevant and translational mouse model of AIMSS to help exploring the cellular and molecular mechanisms of the pathophysiology of AIs toxicity.