Fig.1 Conceptual framework of central sensitization and network homeostasis imbalance in chronic pain. ① Following the transmission of peripheral stimuli, an abnormal increase in neuronal excitability (neuronal hyperexcitability) is first triggered in the dorsal horn neurons of the spinal cord, manifested as enhanced synaptic transmission and disruption of the excitation-inhibition balance, constituting the direct neurophysiological basis for central sensitization; ② Activated neurons further stimulate central microglia and astrocytes (glial activation), which release pro-inflammatory mediators such as IL-1β and TNF-α, as well as reactive oxygen species (ROS), forming a neuroinflammatory amplification loop; ③ Persistent inflammatory signals induce epigenetic reprogramming, which maintains the abnormal expression of inflammatory factors and receptors through mechanisms such as DNA methylation and histone modifications, endowing pain with a "memory" that allows it to persist over the long term; ④ These processes reinforce one another through positive feedback mechanisms, gradually evolving from a single pathway abnormality into a multisystem pathological state. This ultimately leads to an imbalance in the homeostasis of the central pain network, manifested as clinical phenotypes such as hyperalgesia/allodynia, excitation-inhibition imbalance, pro-inflammatory/anti-inflammatory imbalance, and abnormal functional connectivity between brain regions. The arrows indicate the causal and feedback relationships among the various pathological stages.

Fig.2 Molecular network mechanisms of epigenetic-neuroimmune interaction regulating central sensitization[31]: Created with BioGDP.com. Neural injury or inflammatory stimulation activates immune cells in the spinal cord, inducing the activation of astrocytes and microglia. In the epigenetic regulatory pathway, PRMT6 activates HIF-1α through methylation, enhancing glycolysis and inflammatory responses in microglia; miR-101 negatively regulates microglial activation by specifically inhibiting the mTOR signaling pathway. Activated glial cells release pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which on one hand directly enhance glutamatergic synaptic transmission (by upregulating the surface expression of AMPA/NMDA receptors), and on the other hand downregulate KCC2 expression via the BDNF/TrkB pathway, thereby weakening GABAergic inhibition. Together, these mechanisms contribute to the maintenance of abnormal synaptic plasticity and central sensitization. Dotted arrows indicate regulatory relationships, while solid arrows indicate the direction of signal transmission.

Fig.3 ​​Neurobiological mechanisms and regulatory pathways of chronic pain comorbid with anxiety and depression. ① Peripheral level: Noxious signals are transmitted via the dorsal root ganglion (DRG) to the dorsal horn of the spinal cord; ② Spinal cord level: Glial cells are activated and release pro-inflammatory mediators, enhancing the transmission of ascending pain signals; ③ Central level: The CCL2/CCR2 signaling axis mediates the projection of pain signals to emotion-regulating brain regions such as the anterior cingulate cortex (ACC) and the central nucleus of the amygdala; long-term potentiation (LTP) at glutamatergic synapses within the ACC consolidates the pain-emotion coupling state. The gut-brain axis participates in regulation through immune, neural, and endocrine pathways, providing a systematic explanation for the three-dimensional comorbidity of pain, emotion, and metabolism. Solid lines represent pathways supported by substantial experimental evidence, while dashed lines indicate potential regulatory pathways requiring further validation.

Fig.4 ​​Sexual dimorphism mechanisms and clinical translational pathways in chronic pain[31]: Created with BioGDP.com. The left panel illustrates gender-dependent neuroimmune regulatory mechanisms: In males, spinal cord microglia are preferentially activated following nerve injury, and the specific upregulation of apolipoprotein E (ApoE) drives the formation of pro-inflammatory microglial subsets, establishing a pain maintenance pattern dominated by the innate immune system; In female individuals, estrogen modulates the excitation threshold of DRG neurons via ERα/ERβ receptors, while adaptive immune components such as T cells participate in distinct regulatory networks; cyclical fluctuations in estrogen levels are closely associated with dynamic changes in pain sensitivity. Key clinical translation bottlenecks: Current pain research lacks sufficient gender-stratified analysis and high-level evidence-based data, preventing the establishment of guidelines for gender-specific drug dosing, efficacy prediction, and adverse reaction assessment.

Fig.5 ​​Interdisciplinary implementation framework for precision medicine in chronic pain: By Figdraw. This framework integrates the entire pathway of chronic pain management, from basic research to clinical implementation. The bottom layer consists of a multi-level mechanism analysis (molecular—cellular—circuit—network); the middle layer involves technology validation and translation (biomarker integration models, closed-loop neuromodulation, and safety assessment of genetic interventions); and the top layer comprises clinical implementation strategies (tiered diagnosis and treatment, multidisciplinary collaboration, and public health governance). Each level is connected by bidirectional arrows, emphasizing the closed-loop translational logic of "basic discoveries → technological validation → clinical application → clinical feedback → basic research," reflecting a paradigm shift from empirical analgesia toward precision interventions guided by the reshaping of network homeostasis.