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TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Morice, Alyn H.; Sadofsky, Laura R.; Benemei, Silvia; Coppi, Elisabetta; De Logu, Francesco; Di Tommaso, Mariarosaria; Fusi, Camilla; Geppetti, Pierangelo; Li Puma, Simone; Marone, Ilaria M.; Materazzi, Serena; Moneti, Gloriano; Nassini, Romina; Susini, Tommaso; Terreni, Alessandro; Tonello, Raquel

Authors

Alyn H. Morice

Dr Laura Sadofsky L.R.Sadofsky@hull.ac.uk
Lecturer in Respiratory Medicine/ Academic lead for postgraduate training in HYMS

Silvia Benemei

Elisabetta Coppi

Francesco De Logu

Mariarosaria Di Tommaso

Camilla Fusi

Pierangelo Geppetti

Simone Li Puma

Ilaria M. Marone

Serena Materazzi

Gloriano Moneti

Romina Nassini

Tommaso Susini

Alessandro Terreni

Raquel Tonello



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.

Publication Date Dec 1, 2016
Journal Cancer research
Print ISSN 0008-5472
Electronic ISSN 1538-7445
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 76
Issue 23
Pages 7024-7035
APA6 Citation Morice, A. H., Sadofsky, L. R., Benemei, S., Coppi, E., De Logu, F., Di Tommaso, M., …Tonello, R. (2016). TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione. Cancer Research, 76(23), 7024-7035. https://doi.org/10.1158/0008-5472.CAN-16-1492
DOI https://doi.org/10.1158/0008-5472.CAN-16-1492
Keywords Pain and palliative care, Steroid hormones and receptors, Aromatase inhibitors, Androstenedione, TRPA1
Publisher URL http://cancerres.aacrjournals.org/content/76/23/7024.article-info
PMID 27758889
Copyright Statement ©2017 University of Hull
Additional Information Authors' accepted manuscript of article published in: Cancer research, 2017, v.76, issue 23.

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