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Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund\u2019s adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10\u00a0days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.<\/jats:p>","DOI":"10.1177\/17448069221121307","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T01:29:10Z","timestamp":1660699750000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":29,"title":["Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala"],"prefix":"10.1177","volume":"18","author":[{"given":"Richard L","family":"Spinieli","sequence":"first","affiliation":[{"name":"Department of Psychology, School of Philosophy, Science and Literature of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael 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NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janete","family":"Anselmo-Franci","sequence":"additional","affiliation":[{"name":"Department of Basic and Oral Biology, Dental School of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4598-1012","authenticated-orcid":false,"given":"Maral","family":"Tajerian","sequence":"additional","affiliation":[{"name":"Department of Biology, Queens College, City University of New York, Flushing, NY, USA"},{"name":"The Graduate Center, City University of New York, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-2730","authenticated-orcid":false,"given":"Christie RA","family":"Leite-Panissi","sequence":"additional","affiliation":[{"name":"Department of Psychology, School of Philosophy, Science and Literature of Ribeir\u00e3o Preto, 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