Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1

Camilla Fusi, Serena Materazzi, Silvia Benemei, Elisabetta Coppi, Gabriela Trevisan, Ilaria M. Marone, Daiana Minocci, Francesco De Logu, Tiziano Tuccinardi, Maria Rosaria Di Tommaso, Tommaso Susini, Gloriano Moneti, Giuseppe Pieraccini, Pierangelo Geppetti () and Romina Nassini
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Camilla Fusi: Section of Clinical Pharmacology and Oncology, University of Florence
Serena Materazzi: Section of Clinical Pharmacology and Oncology, University of Florence
Silvia Benemei: Section of Clinical Pharmacology and Oncology, University of Florence
Elisabetta Coppi: Section of Clinical Pharmacology and Oncology, University of Florence
Gabriela Trevisan: Laboratory of Biological and Molecular Biology, Graduate Program in Health Sciences, University of the Extreme South of Santa Catarina (UNESC), Santa Catarina
Ilaria M. Marone: Section of Clinical Pharmacology and Oncology, University of Florence
Daiana Minocci: Section of Clinical Pharmacology and Oncology, University of Florence
Francesco De Logu: Section of Clinical Pharmacology and Oncology, University of Florence
Tiziano Tuccinardi: University of Pisa
Maria Rosaria Di Tommaso: Section of Pediatrics, Obstetrics and Gynecology and Nursing
Tommaso Susini: Section of Pediatrics, Obstetrics and Gynecology and Nursing
Gloriano Moneti: Section of Clinical Pharmacology and Oncology, University of Florence
Giuseppe Pieraccini: Section of Clinical Pharmacology and Oncology, University of Florence
Pierangelo Geppetti: Section of Clinical Pharmacology and Oncology, University of Florence
Romina Nassini: Section of Clinical Pharmacology and Oncology, University of Florence

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Use of aromatase inhibitors (AIs), exemestane, letrozole and anastrozole, for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. The electrophilic nature of AIs suggests that they may target the transient receptor potential ankyrin 1 (TRPA1) channel, a major pathway in pain transmission and neurogenic inflammation. AIs evoke TRPA1-mediated calcium response and current in rodent nociceptors and human cells expressing the recombinant channel. In mice, AIs produce acute nociception, which is exaggerated by pre-exposure to proalgesic stimuli, and, by releasing sensory neuropeptides, neurogenic inflammation in peripheral tissues. AIs also evoke mechanical allodynia and decreased grip strength, which do not undergo desensitization on prolonged AI administration. These effects are markedly attenuated by TRPA1 pharmacological blockade or in TRPA1-deficient mice. TRPA1 is a major mediator of the proinflammatory/proalgesic actions of AIs, thus suggesting TRPA1 antagonists for the treatment of pain symptoms associated with AI use.

Date: 2014
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DOI: 10.1038/ncomms6736

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