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However, the identity of the endogenous activator of TRPV1 in this setting is unknown. The arachidonic acid metabolites 12\u2010hydroperoxyeicosatetraenoyl acid (12\u2010HpETE) and 20\u2010hydroxyeicosatetraenoic acid (20\u2010HETE) have emerged as potential endogenous activators of TRPV1. However, whether these lipids underlie TRPV1\u2010mediated neurogenic inflammation remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We analysed human cantharidin\u2010induced blister samples and inflammatory responses in TRPV1 transgenic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In a human cantharidin\u2010blister model, the potent TRPV1 activators 20\u2010HETE but not 12\u2010HETE (stable metabolite of 12\u2010HpETE) correlated with arachidonic acid levels. Similarly, in mice, levels of 20\u2010HETE (but not 12\u2010HETE) and arachidonic acid were strongly positively correlated within the inflammatory milieu. Furthermore, LPS\u2010induced oedema formation and neutrophil recruitment were substantially and significantly attenuated by pharmacological block or genetic deletion of TRPV1 channels, inhibition of 20\u2010HETE formation or SP receptor neurokinin 1 (NK<jats:sub>1<\/jats:sub>) blockade. LPS treatment also increased cytochrome P450 \u03c9\u2010hydroxylase gene expression, the enzyme responsible for 20\u2010HETE production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Taken together, our findings suggest that endogenously generated 20\u2010HETE activates TRPV1 causing C\u2010fibre activation and consequent oedema formation. These findings identify a novel pathway that may be useful in the therapeutics of diseases\/conditions characterized by a prominent neurogenic inflammation, as in several skin diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15726","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T10:55:00Z","timestamp":1636541700000},"page":"1450-1469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["20\u2010hydroxyeicosatetraenoic acid (20\u2010HETE) is a pivotal endogenous ligand for TRPV1\u2010mediated neurogenic inflammation in the skin"],"prefix":"10.1111","volume":"179","author":[{"given":"Alexander","family":"Hamers","sequence":"first","affiliation":[{"name":"William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher 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