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Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti\u2010inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that rapamycin may also have agonist activity on TRPM8 channels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or\n                      <jats:italic>Trpm8<\/jats:italic>\n                      KO mouse DRG neurons, we characterized rapamycin\u2019s effects on TRPM8 channels. We also examined the effects of rapamycin on tearing in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Micromolar concentrations of rapamycin activated rat and mouse TRPM8 channels directly and potentiated cold\u2010evoked responses, effects also observed in human TRPM8 channels. In cultured mouse DRG neurons, rapamycin increased intracellular calcium levels almost exclusively in cold\u2010sensitive neurons. Responses were markedly decreased in\n                      <jats:italic>Trpm8<\/jats:italic>\n                      KO mice or by TRPM8 channel antagonists. Cutaneous cold thermoreceptor endings were also activated by rapamycin. Topical application of rapamycin to the eye surface evokes tearing in mice by a TRPM8\u2010dependent mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant rapamycin. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, rapamycin could be used as an experimental tool in the clinic to explore cold thermoreceptors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16402","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T02:29:56Z","timestamp":1715653796000},"page":"3192-3214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons"],"prefix":"10.1111","volume":"181","author":[{"given":"Jos\u00e9 Miguel","family":"Arcas","sequence":"first","affiliation":[{"name":"Instituto de Neurociencias Universidad Miguel Hern\u00e1ndez\u2010CSIC  San Juan de Alicante 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