Fig. 4.

Mechanisms of acid-induced CIBP in BM microenvironment. The extracellular acidosis derived from cancer cells, tumor-induced osteoclasts, and inflammatory cells in the BM microenvironment directly activate acid-sensing ion channels on the membrane of the nociceptor terminals on sensitive neurons in bone. This nociceptor rapidly converts the noxious stimuli into electrochemical signals and transmits them to brain through dorsal root ganglion (primary afferent neuron) and spinal cord (secondary afferent neuron) to induce pain. In addition to its direct algogenic effect, acidosis also prompts the release of inflammatory and nociceptive mediators (IL6, IL8, TNF, CCL5, IL1b, BDNF, NGF) from the tumor-associated osteoblasts that further enhance CIBP by promoting nerve attraction, hyperalgesia, and nociceptor sensitization