{"doi":"10.1111/bph.70280","title":"Critical role of the mast cell/tryptase/PAR2 axis in anastrozole‐induced pain","abstract":"Abstract Background and Purpose Anastrozole, an aromatase inhibitor, is used to treat postmenopausal women with hormone receptor‐positive breast cancer, but also induces musculoskeletal pain and can lead to therapeutic regimen suspension. Aromatase inhibitors promote the release of pro‐inflammatory substances from sensitised nerve fibres, which might lead to peripheral mast cell activation. Experimental Approach We explore if tryptase released by peripheral mast cells could activate the protease‐activated receptor 2 (PAR2) to sustain anastrozole‐induced painful symptoms. Key Results 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‐induced 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‐1068 and AZ3451, reduced the anastrozole‐induced mechanical allodynia and muscle strength loss. Furthermore, anastrozole did not cause mechanical allodynia and muscle strength loss in global (PAR2 −/− ) or sensory neuron‐specific (PAR2 Na v 1.8 −/− ) PAR2 knockout mice. Local sub‐nociceptive doses of the PAR2 agonists (tryptase, trypsin or 2F) enhanced the anastrozole‐induced mechanical sensitivity in wild‐type mice, which was reduced by pre‐treatment with AZ3451. PAR2 −/− or PAR2 Na v 1.8 −/− mice treated with anastrozole did not respond to local sub‐nociceptive doses of PAR2 agonists. Conclusions and Implications Our results provide a new mechanism underlying anastrozole‐induced pain, highlighting the mast cell/tryptase/PAR2 axis as a therapeutic target to manage painful symptoms.","journal":"British Journal of Pharmacology","year":2025,"id":549429,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":904259,"name":"Raquel Tonello","orcid":"0000-0002-2175-9804","position":1,"is_corresponding":false},{"id":1443646,"name":"Evelyne da Silva Brum","orcid":"0000-0001-6020-8274","position":2,"is_corresponding":false},{"id":1443647,"name":"Georg Becker","orcid":"0009-0007-9784-1111","position":3,"is_corresponding":false},{"id":347884,"name":"Nigel W. Bunnett","orcid":"0000-0003-3367-0644","position":4,"is_corresponding":false},{"id":1096587,"name":"Sara Marchesan Oliveira","orcid":"0000-0003-2960-5284","position":5,"is_corresponding":false},{"id":1378680,"name":"Maria Fernanda Pessano Fialho","orcid":"0000-0001-8899-2099","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41391836","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}