Aromatase Inhibitors Induce Painful-like Musculoskeletal Symptoms in Mice: Behavioral, Molecular and Cellular Characterization

Abstract

Breast cancer is the second most common cancer among women in the U.S. Most tumors are hormone-receptor positive, and patients receive adjuvant endocrine treatment with aromatase inhibitors (AI) to prolong disease-free survival and time-to-recurrence. Unfortunately, AI-associated musculoskeletal symptoms (AIMSS) such as joint pain and muscle stiffness/achiness is a common side-effect of AIs and approximately one-fourth of patients discontinue their therapy because of these side effects. The precise mechanisms of AIMSS are unknown and no clearly recognized therapies exist for prevention or treatment. We therefore characterized a mouse model of AI-induced AIMSS. C57BL/6J adult ovariectomized female mice received oral letrozole (0.5 mg/kg once/day for 15 days). Mice were then evaluated for multiple evoked and spontaneous nociceptive and pain-like behaviors. We also determined if supplementation of 17β-estradiol will reverse AIMSS behaviors. The effects of ketoprofen and duloxetine were tested in this model also. Female mice treated with letrozole show significant mechanical hypersensitivity, disruption of nesting behaviors and reduction of voluntary wheel running as well as rearing and burrowing behaviors. In addition, letrozole-treated DRG neurons showed enhanced excitability compared to vehicle-treated mice. Finally, a significant increase in expression levels of pro-inflammatory cytokines IL-1β, TNFα and IL-6 were observed in the DRGs of mice treated with letrozole. Administration of 17β-estradiol partially reversed these behavioral signs. Furthermore, contrary to ketoprofen, duloxetine showed effectiveness in the model and showed significant preference in the CPP test in letrozole-treated mice but not vehicle group. Our results suggest the AI letrozole induces painful AIMSS symptoms in mice that are partially mediated by estrogens. In addition, our results suggest peripheral neuronal hyperexcitability driven by proinflammatory cytokines at the DRG levels. These results enhance our understanding of AIMSS and facilitate development of novel therapies to treat AIMSS, thereby reducing discontinuation of this breast cancer therapy. Funds from VCU School of Medicine and Massey Cancer Center.