High-dose polystyrene nanoparticles trigger aberrant activation of the MAPK pathway in spinal cord and pain hypersensitivity.

The widespread use of plastic products has led to a serious environmental problem, with nanoplastics ubiquitously contaminating the environment and sustaining human exposure, yet the impacts of nanoplastics on human health remain poorly understood. In this study, based on preliminary epidemiological investigations, we found that abnormal pain perception exists in populations chronically exposed to manufacturing environments that mainly produce polystyrene plastics. Further mechanistic studies demonstrated that high-dose polystyrene nanoparticles (PS NPs) induce pain hypersensitivity and elucidated their molecular underpinnings. Upon high-dose PS NPs exposure, microglia in the spinal dorsal horn internalized a fraction of the PS NPs, which were subsequently found to bind to mitogen-activated-protein-kinases (MAPK) pathway components (ERK, JNK, and p38). Molecular dynamics simulations further suggested that this binding could induce conformational alterations in the MAPK components, potentially enhancing the flexibility of their phosphorylation sites (Thr-X-Tyr) and thereby facilitating activation by upstream kinases. As a canonical inflammatory and pain-associated pathway, MAPK activation elevates neuroinflammatory cascades in the spinal dorsal horn, driving neuronal hyperexcitability and, consequently, pain hypersensitivity. Notably, the PS NPs-induced hypersensitivity was reversed by microglial depletion (PLX5622) and inhibition of the MAPK pathway. Collectively, our findings delineate PS NPs-triggered sensory pathophysiology and establish a proof-of-concept mechanistic nexus between environmental pollutants and aberrant somatosensation.