title: Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1.
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.
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fusi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Benemei
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Coppi
authors.affiliation: Laboratory of Biological and Molecular Biology, Graduate Program in Health Sciences, University of the Extreme South of Santa Catarina (UNESC), Santa Catarina 88806-000, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Marone
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Daiana
authors.initials: D
authors.lastname: Minocci
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Logu
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa 56126, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: Department of Health Sciences, Section of Pediatrics, Obstetrics and Gynecology and Nursing, Florence 50139, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Di Tommaso
authors.affiliation: Department of Health Sciences, Section of Pediatrics, Obstetrics and Gynecology and Nursing, Florence 50139, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Susini
authors.affiliation: 1] Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy [2] Mass Spectrometry Center, University of Florence, Florence 50139, Italy.
authors.forename: Gloriano
authors.initials: G
authors.lastname: Moneti
authors.affiliation: 1] Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy [2] Mass Spectrometry Center, University of Florence, Florence 50139, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pieraccini
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence 50139, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
mesh_terms: D000077384:Anastrozole; D000730:Androstadienes / Q000737:chemistry; D000818:Animals; D047072:Aromatase Inhibitors / Q000737:chemistry*; D001522:Behavior, Animal; D002118:Calcium / Q000737:chemistry; D015220:Calcium Channels / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D000077289:Letrozole; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry; D010146:Pain / Q000139:chemically induced*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000737:chemistry*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009570:Nitriles; D013256:Steroids; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; D014230:Triazoles; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D000077384:Anastrozole; D000077289:Letrozole; D003545:Cysteine; C056516:exemestane; D002118:Calcium