Principal molecular elements in microglial activation during chronic pain.
| Target | Upstream activator(s) | Downstream effect(s) | Role in chronic pain | References |
|---|---|---|---|---|
| P2X4 receptor (P2X4R) | ATP released from neurons; transcription factors IRF8, IRF5 | Activation of the p38 MAPK pathway, release of brain-derived neurotrophic factor (BDNF) | Drives neuropathic pain hypersensitivity by downregulating the KCC2 chloride transporter, thereby altering neuronal chloride gradients and excitability | Tsuda et al. [20], 2016Ulmann et al. [23], 2008 |
| P2X7 receptor (P2X7R) | ATP; possibly other DAMPs | Activation of inflammasome (NLRP3), release of IL-1β | Amplifies neuroinflammation and pain persistence | Inoue and Tsuda [8], 2018Xu et al. [29], 2025Grace et al. [30], 2014 |
| Toll-like receptors (TLR2, TLR4) | DAMPs from injured neurons and glia | Activation of pro-inflammatory transcription pathways and cytokine release | Mediation of neuroinflammation and pain hypersensitivity, with a male-specific role for TLR4 in the spinal cord | Kim et al. [21], 2007Liu et al. [22], 2022 |
| Colony-stimulating factor 1 receptor (CSF-1R) | CSF-1 is released from dorsal root ganglion neurons | Microglial proliferation, activation, and gene expression changes | Facilitates microglial activation and chronic pain development | Guan et al. [25], 2016 |
| Interferon regulatory factors (IRF8, IRF5) | Injury signals leading to transcriptional regulation | Upregulate P2X4R and inflammatory mediators including IL-1β, BDNF | Orchestrate the transcriptional program for reactive microglia, essential for pain hypersensitivity | Masuda et al. [27, 28], 2012 and 2014Mapplebeck et al. [80], 2016 |
| NLRP3 inflammasome | Signals integrated from TLRs and P2X7R activation | Maturation and release of interleukin-1β (IL-1β) | Central mediator of local neuroinflammation and chronic pain | Xu et al. [29], 2025 |
| Cathepsin S | P2X7-p38 MAPK signaling | Cleaves neuronal fractalkine, activating the microglial CX3CR1 pathway | Sustains microglial activation and neuroimmune signaling, amplifying nociception | Inoue and Tsuda [8], 2018Lindia et al. [24], 2005 |
| BDNF | Released upon P2X4R activation | Downregulation of the KCC2 chloride transporter in neurons | Causes disinhibition, neuronal hyperexcitability, and pain hypersensitivity | Coull et al. [26], 2005 |
ATP: adenosine 5’-triphosphate; DAMPs: damage-associated molecular patterns; KCC2: potassium-chloride cotransporter 2; MAPKs: mitogen-activated protein kinases.
SN: Conceptualization, Project administration, Writing—original draft. DMF: Writing—review & editing. AC: Writing—review & editing. GT: Visualization, Writing—review & editing. LD: Visualization, Writing—review & editing. GLB: Writing—review & editing. MI: Visualization. FF: Visualization. FG: Writing—review & editing. MM: Project administration, Methodology, Writing—review & editing. All authors read and approved the submitted version.
The authors declare that there are no conflicts of interest.
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