{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:23Z","timestamp":1792790423736,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Neuroscience","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Drug Abuse","award":["DA023281"],"award-info":[{"award-number":["DA023281"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R34NS121875"],"award-info":[{"award-number":["R34NS121875"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["W81XWH2110410"],"award-info":[{"award-number":["W81XWH2110410"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:p>Mu opioid agonists, the most widely used opioids, produce analgesia, respiratory depression, constipation, and reward leading to substance abuse. Like all opioid receptor family members, mu receptors are Gi\/o-coupled and inhibitory, yet mu-mediated disinhibition of GABAergic neurons propagates downstream activation that differs between naive and dependent animals and across receptor subtypes. Here we used TRAP2\/Ai9 reporter mice, which deposit tdTomato in active neurons via the c-Fos locus, with tissue clearing and light sheet microscopy to map whole-brain neuronal activation after acute morphine (10 mg\/kg), an escalating twice-daily morphine regimen producing dependence, or the NOP receptor agonist Ro 64-6198. Despite Gi\/o coupling, all treatments raised global activation relative to vehicle, though this whole-brain increase reached significance only in males, and acute morphine engaged the largest number of regions, all increased with none decreased. Sex differences were prominent: males were more sensitive than females across treatments, with morphine engaging mainly pain- and reward-related midbrain circuitry in males and hypothalamic circuitry in females. In dependent mice, activation was lower across several regions, including a cluster of cerebellar regions that trended toward being turned off relative to acute morphine. NOP receptor activation produced a far weaker profile. Although chronic morphine produced less activation than acute morphine, it produced more widespread co-activation, and while hub composition differed across conditions, global network organization was preserved. These results reveal whole-brain changes in neuronal activation and establish a TRAP2\/Ai9 model that renders activated regions genetically accessible for future site-directed investigation.<\/jats:p>","DOI":"10.64898\/2026.09.22.753526","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:50:25Z","timestamp":1790643025000},"source":"Crossref","is-referenced-by-count":0,"title":["Whole Brain Cellular Activation After Mu and NOP Receptor Agonism Identifies Differential Regional and Network Consequences"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3756-0365","authenticated-orcid":false,"given":"Madeline","family":"Martinez","sequence":"first","affiliation":[{"name":"Florida Atlantic University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4471-7076","authenticated-orcid":false,"given":"Akihiko","family":"Ozawa","sequence":"additional","affiliation":[{"name":"Florida Atlantic University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4455-7132","authenticated-orcid":false,"given":"Daniel","family":"Van Zant","sequence":"additional","affiliation":[{"name":"Florida Atlantic University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9385-6907","authenticated-orcid":false,"given":"Jake","family":"Thornberry","sequence":"additional","affiliation":[{"name":"Florida Atlantic University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-7573","authenticated-orcid":false,"given":"Lawrence","family":"Toll","sequence":"additional","affiliation":[{"name":"Florida Atlantic University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.22.753526","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:50:25Z","timestamp":1790643025000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.22.753526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.09.22.753526","relation":{},"subject":[],"published":{"date-parts":[[2026,9,28]]},"subtype":"preprint"}}