Neuropathic pain in traumatic brain injury: consequences, mechanisms, and therapeutic avenues

Traumatic brain injury (TBI) is a global health crisis affecting approximately 27 million individuals annually. Nearly half of TBI survivors develop chronic neuropathic pain, with post-traumatic headache representing the most prevalent pain syndrome. Despite substantial advances in understanding TBI pathophysiology, no unified mechanistic framework links acute neuroinflammation to the chronification of post-TBI pain, and no FDA-approved treatment currently targets TBI-specific neuropathic pain. This review synthesizes the cellular and molecular mechanisms underlying neuroinflammation and pain following TBI, with emphasis on the roles of microglia, astrocytes, regulatory T cells, and mast cells in sustaining central sensitization. Proinflammatory cytokines, most notably interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), drive nociceptor sensitization through prostaglandin-dependent and receptor-mediated signaling cascades, with IL-1β having the strongest and most direct evidence for nociceptor sensitization. Dysregulation of calcitonin gene-related peptide (CGRP) and substance P exacerbates post-traumatic headache through trigeminovascular sensitization. The review further integrates evidence on epigenetic modifications, ferroptosis, complement system activation, and descending pain modulatory circuit disruption as contributors to pain chronicity. The three key conclusions of this review are: (1) neuroinflammation and central sensitization, driven by glial activation and cytokine signaling, are the primary sustaining forces of chronic post-TBI pain; (2) epigenetic reprogramming and dysregulation of descending pain modulatory pathways drive long-term pain persistence; and (3) therapeutics including CGRP antagonists, adenosine A3 receptor (A3AR) agonists, GABAergic modulators, and emerging natural compounds such as palmitoylethanolamide (PEA) and myrcene show mechanistic promise. Translating these findings into clinical practice requires addressing TBI heterogeneity, validating pain-specific biomarkers, and designing adequately powered trials for this population.