Objective To observe the expression of purinergic receptor subtype P2X3 ( P2X3) in dorsal root ganglion (DRG) of rats at different stages after injection of streptozotocin ( STZ), and the intervention effect of P2X3 receptor antagonist TNP-ATP in diabetic neuralgia (DNP) rats. Methods ( 1) Six of 20 healthy male SD rats were randomly selected as the normal group, and the other 14 rats were intraperitoneally injected with STZ. Two STZ treated rats without modeling were excluded. The paw withdrawal threshold (PWT) was observed before and 7, 14 and 21 days after modeling. The L4-L6 DRG of rats were collected at the above time points, and the expression of P2X3 positive cells was detected by immunofluorescence. (2) Six of 25 healthy male SD rats were randomly selected as the normal + normal saline (Control + NS) group, and the remaining 19 rats were injected with STZ. One STZ injected rat was excluded. The rats with successfully established DNP were randomly divided into a model + normal saline (DNP + NS) group, model + 50 nmol P2X3 inhibitor TNP-ATP (DNP + 50 nmol TNP-ATP) group, and model + 100 nmol P2X3 inhibitor TNP-ATP (DNP + 100 nmol TNP-ATP) group, with six rats in each group. Fourteen days after STZ injection, the DNP + TNP-ATP group was injected with 100 nmol TNP-ATP solution in the dorsum of the foot, whereas the other two groups were injected with the same volume of NS, and the PWT was observed at 0. 5, 1 and 1. 5 h after injection. The effect of drug injection on PWT was also observed after 7 days. Results (1) Compared with the normal group, fasting blood glucose was significantly increased in rats of the model group on Day 7, Day 14 and Day 21. Compared with the normal group, there was no significant change in the PWT of the model group at Day 7, but there was a significant decrease in PWT at Day 14 and Day 21. Immunofluorescence showed that the expression of P2X3 positive cells on L4 and L5 DRG from the DNP group was significantly increased 7, 14 and 21 days after STZ injection compared with the normal group. (2) Before TNP-ATP intervention, there were no significant differences in the PWT between the DNP + NS, DNP + 50 nmol TNP-ATP and DNP + 100 nmol TNP-ATP groups. Compared with DNP + NS and DNP + 50 nmol TNP-ATP groups, the PWT in the DNP + 100 nmol TNP-ATP group was significantly increased after 0. 5 h intervention, and the effect lasted for 1 h. (3) After continuous injection of TNP-ATP for 7 days, the PWT in the DNP + 100 nmol TNP-ATP group was significantly higher than that in DNP + NS and DNP + 50 nmol TNP-ATP groups. Conclusions The DNP rat model was successfully established by intraperitoneal injection of STZ, and up-regulation of P2X3 expression in the DRG may be involved in the regulation of diabetic neuralgia.