{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:40:46Z","timestamp":1788324046356,"version":"build-2803163510"},"reference-count":77,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T00:00:00Z","timestamp":1724457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Operational Program \u201cCompetitiveness, Entrepreneurship and Innovation\u201d (NSRF 2014\u20132020)","award":["MIS 5047236"],"award-info":[{"award-number":["MIS 5047236"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular\u2019s connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raphe magnus (RMg). In addition, we also identified an extensive insular connection to the parabrachial nucleus (PBN). Although not as extensive, we found a consistent axonal input from the insula to different noradrenergic nuclei, the locus coeruleus (LC), the subcoereuleus (SubCD) and the A5 nucleus. These connections emphasize a prominent relation of the insula with the descending pain modulatory system, which reveals an important role of the insula in pain processing through descending pathways.<\/jats:p>","DOI":"10.3390\/ijms25179185","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T05:16:24Z","timestamp":1724649384000},"page":"9185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Multiple Posterior Insula Projections to the Brainstem Descending Pain Modulatory System"],"prefix":"10.3390","volume":"25","author":[{"given":"Despoina","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Biological Applications and Technology, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0396-4716","authenticated-orcid":false,"given":"Charalampos","family":"Labrakakis","sequence":"additional","affiliation":[{"name":"Department of Biological Applications and Technology, University of Ioannina, 45110 Ioannina, Greece"},{"name":"Institute of Biosciences, University Research Center of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","article-title":"Endogenous and Exogenous Opioids in Pain","volume":"41","author":"Corder","year":"2018","journal-title":"Annu. 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