Neuroinflammation, central sensitization drive chronic post-TBI pain; CGRP antagonists, PEA show therapeutic promise.

Nearly half of Traumatic Brain Injury (TBI) survivors develop chronic neuropathic pain, with post-traumatic headache being most prevalent. Despite advances in understanding TBI pathophysiology, no unified mechanistic framework links acute neuroinflammation to the chronification of post-TBI pain, and no FDA-approved treatment specifically targets TBI-related neuropathic pain. This gap highlights the urgent need to identify key cellular and molecular drivers to develop effective, targeted therapies.

This review synthesizes the cellular and molecular mechanisms underlying neuroinflammation and pain following traumatic brain injury (TBI). It emphasizes the roles of specific cell types like microglia, astrocytes, regulatory T cells, and mast cells in sustaining central sensitization. The authors integrated evidence on various biological processes, including epigenetic modifications, ferroptosis, complement system activation, and disruption of descending pain modulatory circuits, to understand their contributions to pain chronicity.

The review identifies neuroinflammation and central sensitization, primarily driven by glial activation and cytokine signaling, as the main forces sustaining chronic post-TBI pain. Proinflammatory cytokines, notably interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), drive nociceptor sensitization via prostaglandin-dependent and receptor-mediated cascades, with IL-1β showing the strongest evidence. Dysregulation of calcitonin gene-related peptide (CGRP) and substance P exacerbates post-traumatic headache through trigeminovascular sensitization. Epigenetic reprogramming and dysregulation of descending pain modulatory pathways also drive long-term pain persistence. The review's three key conclusions 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. (3) Therapeutics including CGRP antagonists, adenosine A3 receptor (A3AR) agonists, GABAergic modulators, and emerging natural compounds like palmitoylethanolamide (PEA) and myrcene show mechanistic promise.