{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:10:19Z","timestamp":1791216619546,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":759,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2007,1]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>Protease\u2010activated receptor\u20104 (PAR<jats:sub>4<\/jats:sub>), the most recently discovered member of the PARs family, is activated by thrombin, trypsin and cathepsin G, but can also be selectively activated by small synthetic peptides (PAR<jats:sub>4<\/jats:sub>\u2010activating peptide, PAR<jats:sub>4<\/jats:sub>\u2010AP). PAR<jats:sub>4<\/jats:sub>is considered a potent mediator of platelet activation and inflammation. As both PAR<jats:sub>1<\/jats:sub>and PAR<jats:sub>2<\/jats:sub>have been implicated in the modulation of nociceptive mechanisms, we investigated the expression of PAR<jats:sub>4<\/jats:sub>in sensory neurons and the effects of its selective activation on nociception.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach and key results:<\/jats:title><jats:p>We demonstrated the expression of PAR<jats:sub>4<\/jats:sub>in sensory neurons isolated from rat dorsal root ganglia by reverse transcription\u2010polymerase chain reaction and immunofluorescence. We found that PAR<jats:sub>4<\/jats:sub>colocalized with calcitonin gene\u2010related peptide and substance P. We also showed that a selective PAR<jats:sub>4<\/jats:sub>\u2010AP was able to inhibit calcium mobilization evoked by KCl and capsaicin in rat sensory neurons. Moreover, the intraplantar injection of a PAR<jats:sub>4<\/jats:sub>\u2010AP significantly increased nociceptive threshold in response to thermal and mechanical noxious stimuli, while a PAR<jats:sub>4<\/jats:sub>inactive control peptide had no effect. The anti\u2010nociceptive effects of the PAR<jats:sub>4<\/jats:sub>\u2010AP were dose\u2010dependent and occurred at doses below the threshold needed to cause inflammation. Finally, co\u2010injection of the PAR<jats:sub>4<\/jats:sub>\u2010AP with carrageenan significantly reduced the carrageenan\u2010induced inflammatory hyperalgesia and allodynia, but had no effect on inflammatory parameters such as oedema and granulocyte infiltration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>Taken together, these results identified PAR<jats:sub>4<\/jats:sub>as a novel potential endogenous analgesic factor, which can modulate nociceptive responses in normal and inflammatory conditions.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic>(2007)<jats:bold>150<\/jats:bold>, 176\u2013185. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" 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