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

Qi-Yan Feng; Jin-Rong Wei; Meng-Xue Song; Zi-Yue Deng; Yong-Chang Li; Shu-Fen Hu; Fu-Chao Zhang; Hai-Long Zhang; Guang-Yin Xu; Guo-Qin Jiang

doi:10.1016/j.isci.2026.114753

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

iScience. 2026 Jan 20;29(2):114753. doi: 10.1016/j.isci.2026.114753. eCollection 2026 Feb 20.

Authors

Qi-Yan Feng¹, Jin-Rong Wei¹, Meng-Xue Song¹, Zi-Yue Deng^{2

3}, Yong-Chang Li^{2

3}, Shu-Fen Hu^{2

3}, Fu-Chao Zhang^{2

3}, Hai-Long Zhang⁴, Guang-Yin Xu^{2

3}, Guo-Qin Jiang¹

Affiliations

¹ Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
² Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China.
³ Center for Translational Pain Medicine, Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China.
⁴ Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital of Soochow University, Suzhou 215123, China.

Abstract

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.

Keywords: Biological sciences; Cancer; Neuroscience.