Y Li, RY North, LD Rhines, C Esteves Tatsui, G Rao, DD Edwards, RM Cassidy, DS Harrison, CA Johansson, H Zhang and PM Dougherty,
The Journal of neuroscience : the official journal of the Society for Neuroscience, Dec 2017 18
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving paclitaxel. The voltage gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain; in inherited human pain phenotypes; and its gene expression is increased in dorsal root ganglia (DRG) of paclitaxel treated rats. Hence, the potential of change in expression and function of Nav1.7 protein in DRG from rats with paclitaxel related CIPN and from humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP); and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II- (a selective Nav1.7 channel blocker) sensitive sodium currents. Bath applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN; while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain, also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also co-localized in human cells expressing TRPV1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain including chemotherapy (paclitaxel) -induced neuropathic pain.SIGNIFICANCE STATEMENTThis work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 is increased in a pre-clinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anti-cancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact indicating an important novel therapeutic avenue for neuropathic pain as a class.