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In our previous study, early life stress enhanced nerve injury\u2010induced hyperalgesia in adult male and female mice. In the present study, using phosphorylated extracellular signal\u2010regulated kinase (p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>) as a marker of neuronal activation, we examined the effect of early life stress on neuronal function following partial sciatic nerve ligation (<jats:styled-content style=\"fixed-case\">PSL<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Early life stress was induced by maternal separation from 2 to 3\u00a0weeks of age and by social isolation after weaning (<jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content>). Neuropathic pain was induced by <jats:styled-content style=\"fixed-case\">PSL<\/jats:styled-content> at 9\u00a0weeks of age, and p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> expression after light touch stimulation to the ipsilateral paw was measured using immunohistochemistry 1\u00a0week after nerve injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Although <jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content> increased p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> expression in the paraventricular nucleus (<jats:styled-content style=\"fixed-case\">PVN<\/jats:styled-content>) and amygdala of male mice, <jats:styled-content style=\"fixed-case\">PSL<\/jats:styled-content> did not affect p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> expression in control and <jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content> mice. In female mice, increased p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> expression was observed in the medial prefrontal cortex (<jats:styled-content style=\"fixed-case\">mPFC<\/jats:styled-content>) and nucleus accumbens (<jats:styled-content style=\"fixed-case\">NA<\/jats:styled-content>c). Furthermore, p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> expression in the <jats:styled-content style=\"fixed-case\">PVN<\/jats:styled-content> and amygdala was increased in <jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PSL<\/jats:styled-content> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present data suggest that early life stress sex\u2010dependently and site\u2010specifically increases neuronal activity in the brain. In addition, increased neuronal activity in multiplebrain regions of mice subjected to early life stress may enhance hyperalgesia after nerve injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>What does this study add?<\/jats:title><jats:p>Maternal separation and social isolation (<jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content>) increased p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> in the paraventricular nucleus (<jats:styled-content style=\"fixed-case\">PVN<\/jats:styled-content>) and amygdala of male mice. <jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content> increased p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> in the medial prefrontal cortex and nucleus accumbens of female mice. Neuropathic pain increased p\u2010<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> in the <jats:styled-content style=\"fixed-case\">PVN<\/jats:styled-content> and amygdala of female <jats:styled-content style=\"fixed-case\">MSSI<\/jats:styled-content> mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.860","type":"journal-article","created":{"date-parts":[[2016,3,3]],"date-time":"2016-03-03T04:31:25Z","timestamp":1456979485000},"page":"1346-1356","source":"Crossref","is-referenced-by-count":13,"title":["Early life stress induces sex\u2010dependent increases in phosphorylated extracellular signal\u2010regulated kinase in brains of mice with neuropathic pain"],"prefix":"10.1002","volume":"20","author":[{"given":"T.","family":"Nishinaka","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy School of Pharmaceutical Sciences Kobe Gakuin University Kobe 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