The neurons in NAc core receiving ACC excitatory afferents contribute to chronic postoperative pain.

Chronic postoperative pain (CPOP) remains a significant clinical challenge, with central sensitization being an important mechanism. However, the neuronal circuit-mediated mechanisms associated with this disorder are poorly understood. Here, we identified the nucleus accumbens core (AcbC) received excitatory projections from calcium/calmodulin-dependent protein kinase II (CaMKII)-positive neurons in the anterior cingulate cortex (ACC), playing an important role in the development of CPOP. We demonstrated that the AcbC neurons displayed the enhanced responses to both non-nociceptive and nociceptive stimuli following skin/muscle incision and retraction. Furthermore, fiber photometry and electrophysiological recordings confirmed that the activity of the ACC(CaMKII)-AcbC pathway was also elevated after surgery. Inhibition of AcbC neurons or the ACC(CaMKII)-AcbC pathway alleviated pain hypersensitivity in CPOP mice, whereas their activation induced pain phenotypes in naive mice. These findings reveal critical roles for the AcbC neurons and ACC(CaMKII)-AcbC pathway in CPOP pathogenesis, offering potential therapeutic targets for postoperative pain management.