{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:20:17Z","timestamp":1791116417111,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":2738,"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":[[2001,8]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Thrombin, generated in the circulation during injury, cleaves proteinase\u2010activated receptor 1 (PAR1) to stimulate plasma extravasation and granulocyte infiltration. However, the mechanism of thrombin\u2010induced inflammation in intact tissues is unknown. We hypothesized that thrombin cleaves PAR1 on sensory nerves to release substance P (SP), which interacts with the neurokinin 1 receptor (NK1R) on endothelial cells to cause plasma extravasation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PAR1 was detected in small diameter neurons known to contain SP in rat dorsal root ganglia by immunohistochemistry and <jats:italic>in situ<\/jats:italic> hybridization.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Thrombin and the PAR1 agonist TFLLR\u2010NH<jats:sub>2<\/jats:sub> (TF\u2010NH<jats:sub>2<\/jats:sub>) increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> &gt;50% of cultured neurons (EC<jats:sub>50<\/jats:sub>s 24\u2003mu\u2003ml<jats:sup>\u22121<\/jats:sup> and 1.9\u2003\u03bc<jats:sc>M<\/jats:sc>, respectively), assessed using Fura\u20102 AM. The PAR1 agonist completely desensitized responses to thrombin, indicating that thrombin stimulates neurons through PAR1.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Injection of TF\u2010NH<jats:sub>2<\/jats:sub> into the rat paw stimulated a marked and sustained oedema. An NK1R antagonist and ablation of sensory nerves with capsaicin inhibited oedema by 44% at 1\u2003h and completely by 5\u2003h.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In wild\u2010type but not PAR1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, TF\u2010NH<jats:sub>2<\/jats:sub> stimulated Evans blue extravasation in the bladder, oesophagus, stomach, intestine and pancreas by 2\u20138 fold. Extravasation in the bladder, oesophagus and stomach was abolished by an NK1R antagonist.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Thus, thrombin cleaves PAR1 on primary spinal afferent neurons to release SP, which activates the NK1R on endothelial cells to stimulate gap formation, extravasation of plasma proteins, and oedema. In intact tissues, neurogenic mechanisms are predominantly responsible for PAR1\u2010induced oedema.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2001) <jats:bold>133<\/jats:bold>, 975\u2013987; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0704152\">10.1038\/sj.bjp.0704152<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0704152","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T21:57:24Z","timestamp":1106949444000},"page":"975-987","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":116,"title":["Agonists of proteinase\u2010activated receptor 1 induce plasma extravasation by a neurogenic mechanism"],"prefix":"10.1111","volume":"133","author":[{"given":"Lawrence de","family":"Garavilla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Vergnolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Ennes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Steinhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria S","family":"Ossovskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R","family":"D'Andrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeran A","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morley D","family":"Hollenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Andrade\u2010Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel W","family":"Bunnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.19.8964"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02014297"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)46995-5"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.19.12.3014"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01469-3"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.3.821"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(99)01440-6"},{"key":"e_1_2_7_9_1","first-page":"975","article-title":"Expression of monocyte chemotactic protein\u20101 by monocytes and endothelial cells exposed to thrombin","volume":"144","author":"COLOTTA F.","year":"1994","journal-title":"Am. 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