Upregulation of AK7 in ACC-VTA glutamatergic projections contributes to chronic inflammation pain in male mice.

Chronic inflammation pain is a complex pathological condition involving multiple mechanisms in both the peripheral and central nervous systems. Growing evidence indicates that an imbalance in central nervous system function plays a crucial role in the progression of chronic pain, yet the underlying neural circuits and molecular targets remain largely unclear. Here we identify the anterior cingulate cortex (ACC) as a key mediator in chronic inflammation pain. Noxious stimulation significantly increases c-Fos expression and calcium activity in both the ACC and the ventral tegmental area (VTA). Upregulation of adenosine kinase 7 (AK7) in ACC glutamatergic neurons emerges as an important factor in pain pathogenesis: interfering with AK7 expression reduces neuronal activity in the ACC and VTA and alleviates pain-related behaviors, while overexpressing AK7 enhances neuronal activity in these regions and exacerbates pain. Further experiments demonstrate that modulating the activity of VTA glutamatergic neurons can correspondingly reverse the effects of AK7 manipulation on pain phenotypes. In summary, our findings demonstrate that upregulation of AK7 in ACC promotes chronic pain through the ACC-VTA neural circuit.