title: TRPA1 Mediates Aromatase Inhibitor-Evoked Pain by the Aromatase Substrate Androstenedione.
abstract: Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024-35. ©2016 AACR.
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Logu
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.|Department of Pharmacology, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, Brazil.
authors.forename: Raquel
authors.initials: R
authors.lastname: Tonello
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fusi
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Coppi
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Li Puma
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Marone
authors.affiliation: Cardiovascular and Respiratory Studies, The University of Hull, Hull, United Kingdom.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Sadofsky
authors.affiliation: Academic Department of Medicine, Castle Hill Hospital, Cottingham, United Kingdom.
authors.forename: Alyn H
authors.initials: AH
authors.lastname: Morice
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Susini
authors.affiliation: General Laboratory, Careggi University Hospital, Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Terreni
authors.affiliation: Mass Spectrometry Center, University of Florence, Florence, Italy.
authors.forename: Gloriano
authors.initials: G
authors.lastname: Moneti
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Di Tommaso
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy. geppetti@unifi.it.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Benemei
mesh_terms: D000735:Androstenedione / Q000009:adverse effects*; D000818:Animals; D047072:Aromatase Inhibitors / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000737:chemistry*
chemical_list: D047072:Aromatase Inhibitors; D050051:Transient Receptor Potential Channels; D000735:Androstenedione