Objective To investigate the role of the T-cell death associated gene 8 (TDAG8) in pancreatic cancer pain. Methods SW 1990 cells were transplanted into the pancreas of female BALB/c nude mice to establish a pancreatic cancer pain mouse model. Weight measurement and hematoxylin eosin (HE) staining were used to detect the pathological changes of pancreatic tissue. TDAG8-siRNA was intraperitoneally injected into pancreatic cancer pain model mice，and real-time fluorescent quantitative PCR (RT-qPCR) was used to detect the expression of TDAG8 in the spinal dorsal horn tissue. The hunchback score and abdominal skin mechanical pain threshold of each group of mice were detected. Western blotting was used to detect TDAG8, calcitonin gene related peptide (CGRP), substance P (SP), serine/threonine kinase (AKT), p-AKT，mammalian target of rapamycin (mTOR), and p-mTOR protein levels in spinal dorsal horn tissues. AKT pathway inhibitor LY294002 was applied to pancreatic cancer pain model mice, and humpback score and abdominal skin mechanical pain threshold of each group were detected. Western blotting was used to detect the protein levels of CGRP, SP, AKT, p-AKT, mTOR and p-mTOR in spinal dorsal horn tissues. ResultsIn BALB/c nude mice transplanted with SW 1990 cells, body weight was significantly reduced, abnormal acinar cells were observed in pancreatic tissue, TDAG8 mRNA and protein levels were significantly increased in spinal dorsal horn tissue, hump score and mechanical pain threshold were significantly decreased in mice, the protein levels of CGRP, SP, p-AKT, and p-mTOR in the spinal dorsal horn tissue were significantly increased (P<0.05). After the treatment of TDAG8-siRNA and LY294002, the mice′s humpback score decreased and the mechanical pain threshold increased significantly, and the protein levels of CGRP, SP, p-AKT, and p-mTOR in the spinal dorsal horn tissue were significantly decreased (P<0.05). Conclusion Inhibition of TDAG8 can reduce the pain of pancreatic cancer, and its mechanism may be related to the inhibition of the activation of AKT/mTOR signaling pathway.