The complexity and diversity of pain signaling have led to obstacles for prominent treatments due to mechanisms that are not yet fully understood. Among adenosine triphosphate (ATP) receptors, P2X7 differs in many respects from P2X1-6, it plays a significant role in various inflammatory pain, but whether it plays a role in non-inflammatory pain has not been widely discussed. In this study, we utilized major neuropharmacological methods to record the effects of manipulating P2X7 during nociceptive signal transmission in the thalamocingulate circuits. Our results show that regardless of the specific cell type distribution of P2X7 in the central nervous system (CNS), it participates directly in the generated nociceptive transmission, which indicates its apparent functional existence in the major pain transmission path, the thalamocingulate circuits. Activation of P2X7 may facilitate transmission velocity along the thalamocingulate projection as well as neuron firings and synaptic vesicle release in anterior cingulate cortical neurons. Targeting thalamic P2X7 affects glutamate and ATP secretion during nociceptive signal transmission.