Functional upregulation of nav1.8 sodium channels on the membrane of dorsal root Ganglia neurons contributes to the development of cancer-induced bone pain.

Xiao-Dan Liu,Jie Cai,Dong Fang,Jing-Jing Yang,You Wan,Guo-Gang Xing,Joseph Charles Glorioso

doi:10.1371/journal.pone.0114623

Abstract

We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin-resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain.

Highlights

Bone cancer pain resulting from primary tumors or tumors that metastasize to bones is one of the most severe and intractable types of cancer pain, which decreases the quality of life of patients [1]
To explore whether TTX-R sodium channels contribute to the development of cancer-induced bone pain, we first measured TTX-R sodium currents recorded on acutely isolated dorsal root ganglia (DRG) neurons in a rat model of bone cancer pain, by adding TTX (300 nM) to the bath solution to block all TTX-sensitive channels [25]
On day 7 after inoculation, no significant difference was observed on the density of TTX-R sodium current between neurons from rats treated with MRMT-1 tumor cells (96.67¡8.2 pA/pF, n514) and those from rats treated with phosphate-buffered saline (PBS) (97.08¡5.8 pA/pF, n515) (P.0.05, two-way analysis of variance (ANOVA), Figs. 1C, D and G), which is consistent with our previous behavioral findings showing there was no mechanical or thermal pain hypersensitivity at that time [3]

Summary

Introduction

Bone cancer pain resulting from primary tumors or tumors that metastasize to bones is one of the most severe and intractable types of cancer pain, which decreases the quality of life of patients [1]. The mechanisms underlying the development of bone cancer pain remain largely unknown. We and others have found that thermal hyperalgesia and mechanical hypersensitivity in murine models of bone cancer pain are associated with enhanced excitability of primary nociceptive DRG neurons [2, 3]. Aberrant expression patterns of these channels and inherited sodium channelopathies have been linked to neuropathic and inflammatory pain [4]. Adult DRG neurons can express both tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels. Among the latter, the TTX-R sodium channel Nav1.8 is expressed on sensory neurons [5, 6]. Nav1.8 is one of the most attractive targets for the development of new pharmaceutical agents to treat pain

Methods

Results

Conclusion