{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:26:18Z","timestamp":1765369578183,"version":"build-2065373602"},"reference-count":71,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"North Portugal Regional Operational Programme (Norte 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)","award":["Project NORTE-01-0145-FEDER-000008"],"award-info":[{"award-number":["Project NORTE-01-0145-FEDER-000008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund\u2019s adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal\u2013regulated kinases 1 and 2 (pERK1\/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1\/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors.<\/jats:p>","DOI":"10.3390\/ijms21082973","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"2973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-5581","authenticated-orcid":false,"given":"Raquel","family":"Pereira-Silva","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Departamento de Biomedicina\u2013Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5623-8531","authenticated-orcid":false,"given":"Jos\u00e9 Tiago","family":"Costa-Pereira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Departamento de Biomedicina\u2013Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Raquel","family":"Alonso","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Departamento de Biomedicina\u2013Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-7500","authenticated-orcid":false,"given":"Paula","family":"Serr\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Biomedicina\u2013Unidade de Farmacologia e Terap\u00eautica, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"MedInUP\u2013Center for Drug Discovery and Innovative Medicines, University of Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6797-2558","authenticated-orcid":false,"given":"Isabel","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Departamento de Biomedicina\u2013Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2352-3336","authenticated-orcid":false,"given":"Fani L.","family":"Neto","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade da Universidade do Porto (I3S). Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Rua Alfredo Allen 208, 4200-393 Porto, Portugal"},{"name":"Departamento de Biomedicina\u2013Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto. Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1093\/rheumatology\/keh129","article-title":"Patterns of joint pain: Lessons from epidemiology","volume":"43","author":"Birrell","year":"2004","journal-title":"Rheumatology"},{"key":"ref_2","first-page":"S128","article-title":"Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: A Synopsis","volume":"20","author":"Gibofsky","year":"2014","journal-title":"Am. J. Manag. Care"},{"key":"ref_3","first-page":"26","article-title":"Socioeconomic burden of pain in rheumatic disease","volume":"35","author":"Vilen","year":"2017","journal-title":"Clin. Exp. 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