DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Na1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Na1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Na1.7 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 Na1.7 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 Na1.7 associated with spontaneous activity. Na1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Na1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain. This work demonstrates that the expression and function of the voltage-gated sodium channel Na1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Na1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Na1.7 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.

Quantitative differences in neuronal subpopulations between mouse and human dorsal root ganglia demonstrated with RNAscope in situ hybridization

“…At the protein level, Nav1.7 (SCN9A) has been shown to be expressed in the majority of small diameter nociceptors and a small subset of large diameter NF200-positive neurons in rodent [6; 10; 27]. In human, these Nav1.7-protein positive nociceptors co-express TRPV1 and CGRP [27]. While the protein seems to be nociceptor exclusive, single-cell sequencing of mouse DRG demonstrates that Nav1.7 mRNA is expressed in all sensory neurons [47].…”

DNMT3a‐triggered downregulation of K2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

“…Chemotherapy drugs poorly penetrate into the central nervous system, but they have unrestricted access to dorsal root ganglion (DRG) due to the lack of an effective vascular permeability barrier . Chemotherapeutic paclitaxel produced ectopic spontaneous activity in DRG neuronal somata . This abnormal activity, which has been identified as a CIPNP contributor, may be related to the changes in the gene expression at the transcriptional and translational levels in the DRG after chemotherapy drug treatments .…”

“…8,9 Chemotherapeutic paclitaxel produced ectopic spontaneous activity in DRG neuronal somata. [10][11][12][13] This abnormal activity, which has been identified as a CIPNP contributor, [10][11][12][13] may be related to the changes in the gene expression at the transcriptional and translational levels in the DRG after chemotherapy drug treatments. [10][11][12][13][14][15][16][17][18][19] Understanding how chemotherapy drugs drive these changes is essential for improving patient care.…”

Intracerebroventricular Coadministration of Protoxin-II and Trace Elements in Rats Enhances the Analgesic Effect of the 1.7 Voltage-Gate Sodium Channel Blocker

“…Different groups of 7 rats received one of the following formulations: ProTx-II 0.005 mg/kg for the positive control group, 0.9% saline (10 μl) for the negative control group, ProTx-II 0.005 mg/kg + CdCl 2 20 nmol Cd/rat for the Cd group, ProTx-II 0.005 mg/kg + MgCl 2 600 nmol Mg/rat for the Mg group, and ProTx-II 0.005 mg/ kg + ZnCl 2 30 nmol Zn/rat for the Zn group. Behavioural tests were achieved before and after the injection of the substances (15,30,45,60,75, and 90 minutes). Response latencies were automatically recorded.…”

“…A normal value of Cd is essential in pain management because this trace element has been shown to influence dopaminergic, glutamate, acid-sensing ion channels (ASICs), and gamma-aminobutyric acid systems. Cd may be a potent neurotoxin even at reduced doses, while Cd deficit can rise oxidative stress and promote mitochondrial abnormalities [24,25,27], both being mechanisms vastly implicated in pain modulation [29][30][31]. Moreover, Cd may inhibit voltage-gated calcium channels and evoked release of neurotransmitters from the nerves, two other potential mechanisms that can stimulate pain transmission [32].…”