Corticotropin-releasing factor mediates bone cancer induced pain through neuronal activation in rat spinal cord

Corticotropin-releasing factor (CRF) serves as a neuromodulator in the hypothalamic-pituitary-adrenal axis, playing an essential role in depression, anxiety, and pain regulation. However, its biological role in bone cancer induced pain has not been investigated. In the present study, we aimed to elucidate the expression and distribution of CRF in spinal cord using a rodent model of bone cancer pain. Our study showed that implantation of Walker 256 mammary gland carcinoma cells into the tibia of rats significantly increased CRF expression in the spinal cord in a time-dependent manner. The upregulated expression of CRF mainly expressed in the superficial dorsal horn of spinal cord. Moreover, immunofluorescence double staining showed that CRF was extensively colocalized with neurons, but hardly with astrocytes or microglia. In addition, intrathecal injection of CRF receptor antagonist (alpha-helical-CRF) significantly inhibited heat hyperalgesia, mechanical allodynia, and the expression of c-Fos in spinal dorsal horn of bone cancer pain rats. In summary, our study demonstrates that CRF plays an important role in the development and maintenance of bone cancer pain via activation of neurons.