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 “nociceptive neuraxis” 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.