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Intracellularly, calpain I has pro-inflammatory properties but becomes anti-inflammatory when exteriorised into the extracellular space. In this study, the effect of calpain I on joint pain was investigated using the kaolin\/carrageenan model of acute synovitis. Evoked pain behaviour was determined by von Frey hair algesiometry and non-evoked pain was measured using dynamic hindlimb weight bearing. Local administration of calpain I reduced secondary allodynia in the acute inflammation model and this effect was blocked by the cell impermeable calpain inhibitor E-64c. Calpain I also blocked the algesic effect of the protease activated receptor-2 (PAR-2) cleaving enzyme mast cell tryptase. The cell permeable calpain blocker E-64d also produced analgesia in arthritic joints. These data suggest that calpain I produces disparate effects on joint pain viz. analgesia when present extracellularly by disarming PAR-2, and pro-algesic when the enzyme is inside the cell.<\/jats:p>","DOI":"10.1177\/17448069211016141","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:09:56Z","timestamp":1621382996000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Intracellular versus extracellular inhibition of calpain I causes differential effects on pain in a rat model of joint inflammation"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4529-3428","authenticated-orcid":false,"given":"Jason J","family":"McDougall","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, 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