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While in spinal cord their activation is frequently correlated with pain or acute noxious stimuli, supraspinally, this association is not so evident and remains unclear. This study aims to evaluate<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 activation in the spinal cord and brainstem nuclei upon neuropathy and\/or an additional mechanical stimulus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Acute noxious mechanical stimulation was applied in the left hindpaw of anaesthetized<jats:styled-content style=\"fixed-case\">SHAM<\/jats:styled-content>\u2010operated and chronic constriction injured (<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>, neuropathic pain model) rats. Other<jats:styled-content style=\"fixed-case\">SHAM<\/jats:styled-content>or<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>rats did not receive any stimulus. Immunohistochemistry against the phosphorylated isoforms of<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 (<jats:styled-content style=\"fixed-case\">pERK<\/jats:styled-content>1\/2) was performed in lumbar spinal cord and brainstem sections to assess<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the spinal cord, stimulation promoted an increase in<jats:styled-content style=\"fixed-case\">pERK<\/jats:styled-content>1\/2 expression in the superficial dorsal horn of<jats:styled-content style=\"fixed-case\">SHAM<\/jats:styled-content>rats. No significant effects were caused by<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>alone. At supraspinal level, changes in<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 activation induced by<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>were observed in<jats:styled-content style=\"fixed-case\">A5<\/jats:styled-content>, locus coeruleus (<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>), raphe obscurus (<jats:styled-content style=\"fixed-case\">ROb<\/jats:styled-content>), raphe magnus, dorsal raphe (<jats:styled-content style=\"fixed-case\">DRN<\/jats:styled-content>), lateral reticular and paragigantocellularis nucleus.<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>increased<jats:styled-content style=\"fixed-case\">pERK<\/jats:styled-content>1\/2 expression in all these nuclei, with exception of<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>, where a significant decrease was verified. Mechanical noxious stimulation of<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>rats decreased<jats:styled-content style=\"fixed-case\">pERK<\/jats:styled-content>1\/2 expression in<jats:styled-content style=\"fixed-case\">ROb<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">DRN<\/jats:styled-content>, but no further changes were detected in either<jats:styled-content style=\"fixed-case\">SHAM<\/jats:styled-content>\u2010 or<jats:styled-content style=\"fixed-case\">CCI<\/jats:styled-content>\u2010stimulated animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>1\/2 are differentially activated in the spinal cord and in selected brainstem nuclei implicated in nociception, in response to an acute noxious stimulus and\/or to a neuropathic pain 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