Neuroimmune regulation of visceral pain: roles of microglia, purinergic signaling, and neuroinflammation.

Visceral hypersensitivity is a hallmark pathophysiological feature of irritable bowel syndrome, characterized by enhanced perception of visceral stimuli and a reduced pain threshold. Although previous studies have mainly attributed visceral hypersensitivity to peripheral inflammation, visceral afferent sensitization, and psychological stress, these mechanisms do not fully explain the persistent pain and discomfort observed in some patients without overt organic lesions or pronounced inflammation. Accumulating evidence indicates that the spinal cord is not merely a relay site for visceral sensory afferent input, but also a critical central locus for pain modulation and amplification. As resident immune cells of the central nervous system, spinal microglia can be activated by persistent visceral stimulation, inflammation, and stress, thereby contributing to the development and maintenance of visceral hypersensitivity through neuroimmune crosstalk. This review summarizes the role of spinal microglia in the development and progression of visceral hypersensitivity and the associated molecular mechanisms. For the first time in this research field, a two-dimensional reaction-diffusion numerical model was established using COMSOL Multiphysics to simulate the spatiotemporal diffusion and degradation patterns of key signaling molecules, including CSF1, ATP, and BDNF, within the microenvironment of the spinal dorsal horn. The model further incorporates coupled analyses of dynamic changes in microglial activation states and neuronal membrane responses, providing a theoretical basis for quantitatively elucidating microglia-mediated pain sensitization. Evidence indicates that signaling molecules such as ATP, CX3CL1, and CSF1 can drive the activation of microglia in the spinal dorsal horn and induce the release of mediators including TNF-α, IL-1β, and BDNF. These changes enhance excitatory synaptic transmission, weaken inhibitory neurotransmission, and promote spinal and central sensitization. Among these mechanisms, the BDNF-TrkB-KCC2/NMDAR signaling axis represents a key molecular pathway underlying microglia-mediated pain amplification. Furthermore, peripheral factors, including intestinal inflammation, psychological stress, and gut microbiota dysbiosis, may further regulate spinal microglial reactivity through the gut-brain axis, thereby exacerbating visceral hypersensitivity. This review not only summarizes recent advances in understanding the involvement of spinal microglia in visceral hypersensitivity, but also provides a theoretical basis for mechanistic studies and targeted interventions in other neuroinflammation-related pathological processes and chronic pain disorders.