Prelimbic cortex-basolateral amygdala glutamatergic circuit drives cancer-induced bone pain in mice.

Cancer-induced bone pain (CIBP), resulting from bone metastases, is excruciating and lacks effective treatment. Previous studies on CIBP mechanisms mainly focused on the peripheral nervous system and spinal cord, with limited attention to the brain. This study investigates the prelimbic cortex (PrL) to basolateral amygdala (BLA) circuit in regulating CIBP in female mice. CIBP models were established by injecting E0771 cells into the tibias of C57BL/6J female mice. c-Fos expression and calcium activity in BLA(Glu) neurons were significantly elevated in CIBP models. Optogenetic inhibition of either BLA(Glu) neurons or PrL(Glu) neurons projecting to BLA increased pain thresholds. The PrL(Glu)-BLA(Glu) projection was activated by CIBP, and chemogenetic inhibition of BLA(Glu) neurons reversed this overactivation and pain thresholds. Glutamate probe analysis showed excessive glutamate release in the BLA, which was reduced by the chemical inhibition of the PrL-BLA circuit. This study identifies a PrL(Glu)-BLA(Glu) circuit controlling CIBP, offering new therapeutic insights.