<p>The substantial contribution of glial cells, particularly astrocytes, in the progression of chronic pain is increasingly acknowledged in the spinal dorsal horn. However, the precise alterations and roles of astrocytes in the midline nuclei of the thalamus during the development of chronic pain remain unclear. In our investigation, spared nerve injury (SNI) induced mechanical pain hypersensitivity in mice, which was associated with the activation and proliferation of astrocytes in the posterior region of the paraventricular thalamic nucleus (pPVT). The chemogenetic activation of astrocyte activity was observed to induce pain hypersensitivity, whereas the inhibition of astrocyte activity was found to alleviate pain. To elucidate the phenotypic regulatory mechanisms of astrocytes, a variety of techniques were employed, including immunofluorescence staining, Western blot analysis, and RT-qPCR. It was confirmed that the activated and proliferating astrocytes within the pPVT in the SNI model were predominantly A1-reactive astrocytes, as evidenced by the expression of complement C3. It is noteworthy that the blockade of the C3a receptor (C3aR) resulted in a significant reduction in pain perception in the SNI mouse model, accompanied by a decrease in the release of pro-inflammatory factors. In conclusion, our results demonstrate that the activation and proliferation of reactive A1 astrocytes in the pPVT are involved in the pathogenesis of SNI. Consequently, targeting type A1 astrocytes may offer a potential strategy to alleviate chronic pain.</p>