01/02/2026
Just published 🔥
𝗣𝗮𝗶𝗻 𝗮𝗻𝗱 𝘁𝗵𝗲 𝗶𝗺𝗺𝘂𝗻𝗲 𝘀𝘆𝘀𝘁𝗲𝗺
⚖️ Pain is increasingly understood as a multidimensional phenomenon arising from dynamic interactions between the nervous and immune systems. Early conceptual frameworks framed pain largely as a neurocentric process; however, seminal work in neuroimmunology demonstrated that immune signaling plays a critical role in both the initiation and persistence of pain (https://pubmed.ncbi.nlm.nih.gov/36775098/, https://pubmed.ncbi.nlm.nih.gov/12270950/). Building on this paradigm, recent research has highlighted the importance of neuroinflammation across nociceptive, neuropathic, and nociplastic pain states (https://pubmed.ncbi.nlm.nih.gov/36775098).
📘 A brand-new narrative review by Hodges et al. (2026, https://www.sciencedirect.com/science/article/pii/S2468781225002322) synthesizes current evidence on neuro-immune mechanisms underlying chronic pain and discusses implications for mechanism-based treatment approaches. The authors present a comprehensive narrative review examining how interactions between immune cells and the nervous system contribute to the development and maintenance of chronic pain. Pain should not be viewed solely as a neuronal output but rather as the product of continuous bidirectional signaling between neurons and immune cells across the peripheral and central nervous systems.
📊 Immune mediators—such as cytokines, chemokines, prostaglandins, reactive oxygen species, and autoantibodies—modulate nociceptor excitability at multiple anatomical levels, including peripheral tissues, peripheral nerves, dorsal root ganglia, the spinal cord, and supraspinal brain regions. These neuro-immune interactions differ across pain phenotypes. In neuropathic pain, nerve injury triggers local immune activation that expands along the neuraxis, creating self-sustaining feed-forward loops between immune cells, glia, and hyperexcitable neurons. In nociceptive inflammatory conditions such as rheumatoid arthritis and osteoarthritis, tissue-driven inflammation initially dominates but may progressively transition toward central neuroinflammatory and nociplastic mechanisms.
❎ A key contribution on pain chronicity seems to be a failure of inflammatory resolution rather than mere persistence of inflammation. Immune and glial cells are shown to play dual roles: while early pro-inflammatory responses are essential for tissue repair, insufficient engagement of anti-inflammatory and pro-resolving pathways promotes maladaptive plasticity and long-term pain. Specialized pro-resolving mediators, regulatory immune cells, and anti-inflammatory cytokines (e.g., IL-10) are critical modulators of pain resolution. Pain chronification may be viewed as a failure of anti-inflammatory processes to bring proinflammation to resolution.
🐁The review further discusses translational challenges, noting that much mechanistic knowledge derives from animal models that incompletely capture the complexity of human chronic pain. Nonetheless, emerging human evidence—from tissue studies, transcriptomics, and neuroimaging using PET markers of glial activation —supports a meaningful role of neuroinflammation in clinical pain conditions, particularly nociplastic pain.
💊 Finally, precision pain management strategies that align treatments with dominant neuro-immune mechanisms are needed. Both pharmacological and non-pharmacological interventions (including exercise, diet, and behavioral therapies) are proposed to exert their effects partly through modulation of immune activity. An improved mechanistic classification of pain is essential to matching the right treatment to the right patient and advancing personalized pain care.
📷 Figure: Overview of key neuroimmune processes at the level of the tissues, and the peripheral and central nervous systems.
