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The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu\u2010opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1\u03b1, IL1\u03b2, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1\u2010positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose\u2010dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO\u2010induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia\u2013MOR relationship could be pivotal to unravel some inflammatory pain\u2010induced comorbidities related to MCLS dysfunction.<\/jats:p>","DOI":"10.1002\/glia.24374","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T10:03:54Z","timestamp":1680689034000},"page":"1906-1920","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Focal mu\u2010opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3418-3135","authenticated-orcid":false,"given":"Javier","family":"Cuitavi","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Technology and Parasitology University of Valencia  Avda. 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