Functional up-regulation of Nav1.8 sodium channel on dorsal root ganglia neurons contributes to the induction of scorpion sting pain

Abstract

BmK I, purified from the venom of scorpion Buthus martensi Karsch (BmK), is a receptor site-3-specific modulator of voltage-gated sodium channels (VGSCs) and can induce pain-related behaviors in rats. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 contributes to most of the sodium current underlying the action potential upstroke in dorsal root ganglia (DRG) neurons and may serve as a critical ion channel targeted by BmK I. Herein, using electrophysiological, molecular, and behavioral approaches, we investigated whether the aberrant expression of Nav1.8 in DRG contributes to generation of pain induced by BmK I. The expression of Nav1.8 was found to be significantly increased at both mRNA and protein levels following intraplantar injection of BmK I in rats. In addition, the current density of TTX-R Nav1.8 sodium channel is significantly increased and the gating kinetics of Nav1.8 is also altered in DRG neurons from BmK I-treated rats. Furthermore, spontaneous pain and mechanical allodynia, but not thermal hyperalgesia induced by BmK I, are significantly alleviated through either blockade of the Nav1.8 sodium channel by its selective blocker A-803467 or knockdown of the Nav1.8 expression in DRG by antisense oligodeoxynucleotide (AS-ODN) targeting Nav1.8 in rats. Finally, BmK I was shown to induce enhanced pain behaviors in complete freund's adjuvant (CFA)-inflamed rats, which was partly due to the over-expression of Nav1.8 in DRG. Our results suggest that functional up-regulation of Nav1.8 channel on DRG neurons contributes to the development of BmK I-induced pain in rats.

Transmembrane protein 100 is expressed in neurons and glia of dorsal root ganglia and is reduced after painful nerve injury

“…22,36,39,64 The percentage of CGRP-positive DRG neurons is consistently increased in various inflammatory pain models, accompanied by functional activation of CGRP + and IB4 + neurons. 1,9,18,30,66,71,72 Our data cannot indicate if there is a causal link between increased number and/or functionally activated populations of CGRP + and IB4 + neurons and the upregulated Tmem100 expression in inflammatory pain. In contrast to inflammatory pain, our data found a significant downregulation of Tmem100 protein in axotomized sensory neurons in the neuropathic pain models.…”

“…32,37,50,64 For instance, IB4- and CGRP-positive small-sized DRG neurons are either functionally activated or increased in proportion in various inflammatory pain models. 1,9,18,30,66,71,72 Complete Freund adjuvant (CFA) inflammation increases CGRP in the innervating DRG, and the proportion and size of DRG neurons with detectable CGRP is increased after inflammation ascribed to increased CGRP release, 54,63 and more IB4 neurons have detectable CGRP expression after inflammation. 63 By contrast, IB4- and CGRP-positive neuron populations are often decreased significantly because of peripheral nerve axotomy in neuropathic pain.…”

Chemical and Biological Tools for the Study of Voltage‐Gated Sodium Channels in Electrogenesis and Nociception

“…Neuropathic pain can be induced in select Na V KO models; some of these findings undercut previously established conclusions (from knockdown studies) regarding the involvement # [216][b] -# [220,211,217][b] --Sciatic nerve entrapment ---# [212][c] --Chronic compression DRG -# [216][b] ----Spinal cord contusion # [213,219] -----Spared nerve injury NE [239] , # [238][a] -----L5/L6 spinal nerve ligation -# [215][b] -# [211,221,222] NE [222] -Chemotherapy -# [48] -NE [211] # [191] -Diabetes # [214][a] -----Inflammatory Complete Freund's Adjuvant --# [224] # [211,228] NE [228] -Zymosan -# [229][b] ----Carrageenan ----# [190] -Acetic/citric acid --# [223][a] # [226] --PGE2 ---# [227] --Imiquimod -----# [230][d] Other Incision -# [231][c] NE [211] --Burn --# [232][c] ---Cancer -----# [233][c] Venom -# [234][c] -# [235] --# = reduced pain-associated behavior. NE = no effect on pain-associated behavior.…”

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

“…Its activity involves the TTX-S Nav1.6 and TTX-R Nav1.8 channels which are over-expressed when BmK I is administered to rodents [ 117 ]. BmK I potentiates Nav1.6 and Nav1.8 currents revealing an important role for these channels in the modulation of spontaneous pain and mechanical allodynia [ 118 - 120 ]. During the process of hyperalgesia and pain sensitization induced by BmK I, it has been shown that both neuronal 5-HT3AR signaling pathway and microglia, with up-regulation of P2X7 receptors and interleukin 1β, are activated [ 121 , 122 ].…”