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Aromatase inhibitors promote the release of pro\u2010inflammatory substances from sensitised nerve fibres, which might lead to peripheral mast cell activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We explore if tryptase released by peripheral mast cells could activate the protease\u2010activated receptor 2 (PAR2) to sustain anastrozole\u2010induced painful symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Anastrozole caused mechanical allodynia, muscle strength loss, and increased mast cell number and tryptase levels in the plantar tissue of male C57BL\/6 mice. Depletion (using compound 48\/80) or stabilisation (using ketotifen fumarate) of mast cells prevented anastrozole\u2010induced mechanical allodynia and muscle strength loss. Compound 48\/80 also prevented the increase in the number of mast cells in the plantar tissue. Tryptase inhibitors nafamostat and gabexate, or PAR2 inhibitors ENMD\u20101068 and AZ3451, reduced the anastrozole\u2010induced mechanical allodynia and muscle strength loss. Furthermore, anastrozole did not cause mechanical allodynia and muscle strength loss in global (PAR2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) or sensory neuron\u2010specific (PAR2 Na\n                      <jats:sub>v<\/jats:sub>\n                      1.8\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) PAR2 knockout mice. Local sub\u2010nociceptive doses of the PAR2 agonists (tryptase, trypsin or 2F) enhanced the anastrozole\u2010induced mechanical sensitivity in wild\u2010type mice, which was reduced by pre\u2010treatment with AZ3451. PAR2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      or PAR2 Na\n                      <jats:sub>v<\/jats:sub>\n                      1.8\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice treated with anastrozole did not respond to local sub\u2010nociceptive doses of PAR2 agonists.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Our results provide a new mechanism underlying anastrozole\u2010induced pain, highlighting the mast cell\/tryptase\/PAR2 axis as a therapeutic target to manage painful symptoms.<\/jats:p>\n                  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