Beyond neurons: satellite glial cells in chronic neuropathic pain
Aims: Satellite glial cells (SGCs), which surround sensory neurons in the dorsal root ganglion (DRG), become persistently activated following peripheral nerve injury and contribute to the neuroinflammatory environment associated with chronic pain. Huang et al. investigated the role of FGR, a Src-family non-receptor tyrosine kinase previously implicated in inflammatory signaling, in this process. Specifically, they examined whether FGR contributes to sustained SGC activation and neuropathic pain and explored the molecular mechanisms linking FGR to NF-κB signaling.
Methods: The authors combined several mouse models of peripheral nerve injury with molecular, pharmacological, genetic, and behavioral approaches. FGR expression and localization were examined in mouse and non-human primate DRG. Pharmacological inhibition and SGC-targeted knockdown or overexpression of FGR were used to assess its contribution to pain, while in vitro and molecular experiments investigated its interaction with NF-κB/p65 signaling.
Results: Peripheral nerve injury persistently increased FGR expression in DRG SGCs in both mice and non-human primates. Inhibition or knockdown of FGR reduced mechanical and thermal hypersensitivity in male and female mice, whereas SGC-specific FGR overexpression was sufficient to induce pain-like behaviors and increase inflammatory cytokine production. Mechanistically, FGR prevented PP2α-mediated dephosphorylation of p65, sustaining NF-κB activation. Activated p65, in turn, increased Fgr transcription, establishing a self-reinforcing FGR/p65 inflammatory loop.
Conclusions: The study identifies an FGR/p65 positive feedback loop in SGCs that may help explain how neuroinflammation persists after peripheral nerve injury. Targeting FGR could therefore provide a strategy to interrupt sustained glial activation and chronic neuropathic pain.
Comments. A particularly interesting aspect of this study is that it shifts attention away from the neuron as the sole therapeutic target in neuropathic pain. Rather than simply showing that SGCs become reactive after nerve injury, the authors identify a molecular mechanism that could explain how this reactive state is maintained over time. The finding that FGR is increased in SGCs across different injury models and also in non-human primates strengthens the biological relevance of the pathway. Moreover, showing that SGC-specific FGR overexpression can itself induce pain-like behavior provides compelling evidence for a functional contribution of these cells. However, the translational step remains substantial: FGR inhibition was not tested therapeutically in primates, and the consequences of prolonged systemic inhibition are unknown. Nevertheless, the study reinforces the importance of considering the neuronal microenvironment, and particularly neuron–glia interactions, when investigating mechanisms and potential treatments for chronic neuropathic pain.
Stéphanie Eid
Reference. Huang Y, He Y, Wang Z, Zhang F, Han M, Guo X, Xie Y, Wang J, Ma X, Dan J, Deng Y, Wu H, Hu H, Wang J, Yu L, Jiang BC, Yan M, Ma L. A positive feedback loop between FGR and p65 sustains satellite glial cell activation and chronic neuropathic pain. Cell Rep. 2026 Feb 24;45(2):116899. doi: 10.1016/j.celrep.2025.116899. Epub 2026 Jan 22. PMID: 41575848.
