{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:07:27Z","timestamp":1787242047030,"version":"build-2736575974"},"reference-count":93,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology (DST), India","award":["DST\/INSPIRE Fellowship\/ IF180166"],"award-info":[{"award-number":["DST\/INSPIRE Fellowship\/ IF180166"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Neuropathic pain (NP) arises from maladaptive changes in peripheral and central nociceptive circuits, yet molecular alterations spanning the entire pain neuraxis remain poorly understood. Neuroinflammation is increasingly recognized as a central mechanism in NP chronification, yet the region-specific molecular events linking immune activation to affective pain processing remain inadequately defined. In this study, we employed high-resolution LC-HRMS-based quantitative proteomics to investigate chronic constriction injury (CCI)-induced molecular alterations in the sciatic nerve (SN), spinal cord (SC), and orbitofrontal cortex (OFC) of male Wistar rats, a region critical for affective and cognitive pain modulation. Behavioral assessments confirmed the development of NP phenotypes and motor deficits. Proteomic profiling revealed exclusive and differentially expressed proteins enriched in neuroinflammatory pathways across all regions. S100 proteins (S100A8 and S100B) were significantly elevated in SN, SC, and OFC, as confirmed by immunofluorescence. Their up-regulation coincided with increased astrocyte (GFAP) and microglial (Iba-1) activation, highlighting a pervasive inflammatory milieu. Intriguingly, the OFC proteome demonstrated marked up-regulation of dopamine-regulating proteins and positive regulation of dopaminergic neurotransmission, suggesting involvement of reward-related analgesic circuits. Together, our findings delineate a \u201cnociceptive neuraxis\u201d driven by neuroimmune activation and neuromodulatory adaptations that interfaces with dopaminergic signaling to influence sensory and affective components of pain. This integrative molecular map highlights potential therapeutic targets, including glial-derived S100 proteins and dopamine modulators for the comprehensive management of NP.<\/jats:p>","DOI":"10.3390\/cells15030290","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T09:02:01Z","timestamp":1770195721000},"page":"290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Integrative Proteomics Reveal Neuroimmune and Dopaminergic Alterations Across the Nociceptive Neuraxis in Neuropathic Pain"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8728-2650","authenticated-orcid":false,"given":"Shreyasi","family":"Majumdar","sequence":"first","affiliation":[{"name":"Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India"},{"name":"Department of Pharmaceutical Technology, School of Health and Medical Sciences, Adamas University, Kolkata 700126, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0198-6863","authenticated-orcid":false,"given":"Santosh Kumar","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India"},{"name":"Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Dande","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research, Hajipur 844102, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod Kumar","family":"Yata","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Allied and Healthcare Sciences, Malla Reddy University, Hyderabad 500100, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khushboo","family":"Choudhary","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research, Hajipur 844102, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramalingam","family":"Peraman","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research, Hajipur 844102, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-3954","authenticated-orcid":false,"given":"Nitesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"National Institute of Pharmaceutical Education and Research, Hajipur 844102, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sairam","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. 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