Figure 7. Graphical summary of the proposed model of the induction of pain and of hyperalgesia and nociceptor sensitization in the BM microenvironment.

In the BM microenvironment, carcinoma cells and tumor-induced osteoclasts pump in the extracellular space a high amount of protons that on one side stimulate ion channels on the membrane of the nociceptor terminal in bone, on the other side, promote the release of inflammatory and nociceptive mediators from the tumor-associated mesenchymal cells, including MSCs, HOBs, and CAFs that further enhance CIBP by promoting hyperalgesia and nociceptor sensitization.