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Several mechanisms underlie PEA actions, among which the \u201centourage\u201d effect, consisting of PEA potentiation of endocannabinoid signaling at either cannabinoid receptors or transient receptor potential vanilloid type-1 (TRPV1) channels. Here, we report novel molecular mechanisms through which PEA controls mast cell degranulation and substance P (SP)-induced histamine release in rat basophilic leukemia (RBL-2H3) cells, a mast cell model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      RBL-2H3 cells stimulated with SP were treated with PEA in the presence and absence of a cannabinoid type-2 (CB2) receptor antagonist (AM630), or a diacylglycerol lipase (DAGL) enzyme inhibitor (OMDM188) to inhibit the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The release of histamine was measured by ELISA and \u03b2-hexosaminidase release and toluidine blue staining were used as indices of degranulation. 2-AG levels were measured by LC-MS. The mRNA expression of proposed PEA targets (\n                      <jats:italic>Cnr1, Cnr2<\/jats:italic>\n                      ,\n                      <jats:italic>Trpv1<\/jats:italic>\n                      ,\n                      <jats:italic>Ppara<\/jats:italic>\n                      and\n                      <jats:italic>Gpr55<\/jats:italic>\n                      ), and of PEA and endocannabinoid biosynthetic (\n                      <jats:italic>Napepld, Dagla<\/jats:italic>\n                      and\n                      <jats:italic>Daglb<\/jats:italic>\n                      ) and catabolic (\n                      <jats:italic>Faah<\/jats:italic>\n                      ,\n                      <jats:italic>Naaa<\/jats:italic>\n                      and\n                      <jats:italic>Mgl<\/jats:italic>\n                      ) enzymes were also measured. The effects of PEA on the activity of DAGL-\u03b1 or -\u03b2 enzymes were assessed in COS-7 cells overexpressing the human recombinant enzyme or in RBL-2H3 cells, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SP increased the number of degranulated RBL-2H3 cells and triggered the release of histamine. PEA counteracted these effects in a manner antagonized by AM630. PEA concomitantly increased the levels of 2-AG in SP-stimulated RBL-2H3 cells, and this effect was reversed by OMDM188. PEA significantly stimulated DAGL-\u03b1 and -\u03b2 activity and, consequently, 2-AG biosynthesis in cell-free systems. Co-treatment with PEA and 2-AG at\n                      <jats:italic>per se<\/jats:italic>\n                      ineffective concentrations downmodulated SP-induced release of histamine and degranulation, and this effect was reversed by OMDM188.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Activation of CB2 underlies the inhibitory effects on SP-induced RBL-2H3 cell degranulation by PEA alone. We demonstrate for the first time that the effects in RBL-2H3 cells of PEA are due to the stimulation of 2-AG biosynthesis by DAGLs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-019-1671-5","type":"journal-article","created":{"date-parts":[[2019,12,26]],"date-time":"2019-12-26T09:03:33Z","timestamp":1577351013000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity"],"prefix":"10.1186","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-3987","authenticated-orcid":false,"given":"Stefania","family":"Petrosino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniello","family":"Schiano Moriello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Verde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Allar\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Imperatore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Ligresti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali Mokhtar","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio Filippo","family":"Peritore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio Arturo","family":"Iannotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Di Marzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,26]]},"reference":[{"key":"1671_CR1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1084\/jem.100.5.425","volume":"100","author":"AF Coburn","year":"1954","unstructured":"Coburn AF, Graham CE, Haninger J. 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