Cortical prostaglandin D2 contributes to behavioral sensitization and anxiety in peripheral inflammation.

Post-injury inflammation can induce abnormal sensory perception and negative emotions. Previous studies have focused on peripheral and spinal prostaglandins (PGs) in response to chronic pain. Substantially, less is known about the role of PGs in the cortex. Here, we found that lipocalin-type prostaglandin D (PGD2) synthase was upregulated in the anterior cingulate cortex (ACC) of mice after peripheral inflammation. At the synaptic level, excitatory glutamatergic transmission was selectively enhanced in both the thalamic- and the insular-ACC pathways. These enhanced responses were reversed by blocking PGD2 receptor DP1. Blocking DP1 in the ACC reduced mechanical and cold hypersensitivity and anxiety-like behaviors after peripheral inflammation. Furthermore, activating NMDARs-AC1 signaling produced L-PGDS. Our results provide direct evidence that the PGD2-DP1 pathway contributes to cortical sensitization and reveals a potential therapeutic target for the early phase of peripheral inflammation.