The Role of Protease-activated Receptor 2 in Chemotherapy- Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of chemotherapy treatment that can severely affect patients’ quality of life and survival rate. Currently, no effective therapeutics exist to either treat or prevent CIPN, partly due to an incomplete understanding of the underlying etiology. Following chemotherapy treatment, immune system activation and increased immune cell infiltration into the dorsal root ganglion (DRG) and epidermis have been observed. Proteases released by these immune cells have been proposed as a possible driver for CIPN pain by acting on protease-activated receptor 2 (PAR2) on nociceptors. PAR2 is a G-protein coupled receptor (GPCR) that is activated by proteolytic cleavage of its N- terminus and has been shown to be implicated in chronic pain. The central goal of our research was to test the therapeutic potential of targeting PAR2 in the context of CIPN pain. Our data revealed that PAR2-mechanical and spontaneous nociception is dependent on a small subpopulation of sensory neurons and that this subpopulation of sensory neurons also mediate CIPN nociception, changes in nerve fiber density in the epidermis, and satellite glial cell activation. Blocking PAR2 with an antagonist, C781, transiently reversed mechanical allodynia in established CIPN. These findings highlight PAR2 as a possible therapeutic target for the treatment of CIPN pain and future research should focus on improving the pharmacokinetic properties of PAR2 antagonists.