@article { , 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.}, doi = {10.1158/0008-5472.CAN-16-1492}, eissn = {1538-7445}, issn = {0008-5472}, issue = {23}, journal = {Cancer research}, pages = {7024-7035}, publicationstatus = {Published}, publisher = {American Association for Cancer Research}, url = {https://hull-repository.worktribe.com/output/448985}, volume = {76}, keyword = {Health and Health Inequalities, Pain and palliative care, Steroid hormones and receptors, Aromatase inhibitors, Androstenedione, TRPA1}, year = {2016}, author = {Morice, Alyn H. and Sadofsky, Laura R. and Benemei, Silvia and Coppi, Elisabetta and De Logu, Francesco and Di Tommaso, Mariarosaria and Fusi, Camilla and Geppetti, Pierangelo and Li Puma, Simone and Marone, Ilaria M. and Materazzi, Serena and Moneti, Gloriano and Nassini, Romina and Susini, Tommaso and Terreni, Alessandro and Tonello, Raquel} }