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To uncover a possible relationship between the slow\u2010onset substance P (SP) release and increased ERK1\/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4\u00a0\u03bcg\/mL in microdialysis fiber, 1\u00a0\u03bcL\/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3\u00a0h of SP reduced the duration of \u2018tonic\u2019 phase nociception, and this SP effect was mediated by neurokinin 1 (NK1) receptors since pre\u2010treatment with NK1 receptor antagonist CP96345 (10\u00a0\u03bcM) blocked the effect of SP infusion. However, formalin\u2010induced \u2018tonic\u2019 phase nociception was significantly prolonged following acute injection of the MAP\/ERK kinase 1\/2 inhibitor PD0325901 (100\u00a0pmol) by microinjection. The coinfusion of SP and PD0325901 significantly increased the \u2018tonic\u2019 phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP\u2010NK1 receptor\u2013ERK1\/2 system.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12938-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Noxious stimulation induces a slow\u2010onset substance P (SP) release as a volume transmitter, activating extra\u2010synaptic NK1 receptors, and evokes phosphorylation of extracellular signal\u2010regulated kinase (ERK) 1\/2. The SP\u2010NK1\u2010ERK1\/2 system in the striatum decreases tonic nociception.<\/jats:p>","DOI":"10.1111\/jnc.12938","type":"journal-article","created":{"date-parts":[[2014,8,30]],"date-time":"2014-08-30T08:51:45Z","timestamp":1409388705000},"page":"755-766","source":"Crossref","is-referenced-by-count":11,"title":["Continuous infusion of substance P into rat striatum alleviates nociceptive behavior via phosphorylation of extracellular signal\u2010regulated kinase 1\/2"],"prefix":"10.1111","volume":"131","author":[{"given":"Yoki","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Izumi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Fukushige","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyohei","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimitsu","family":"Morioka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Graduate School of Biomedical &amp; Health Sciences Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldric","family":"Hama","sequence":"additional","affiliation":[{"name":"Hamamatsu Pharma Research, Inc. 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