Drg voltage-gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain

Yan Li, Robert Y. North, Laurence D. Rhines, Claudio Esteves Tatsui, Ganesh Rao, Denaya D. Edwards, Ryan M. Cassidy, Daniel S. Harrison, Caj A. Johansson, Hongmei Zhang, Patrick M. Dougherty

Research output: Contribution to journalArticle

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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 (Nav1.7) 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 Nav1.7 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 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 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 Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.

Original languageEnglish (US)
Pages (from-to)1124-1136
Number of pages13
JournalJournal of Neuroscience
Volume38
Issue number5
DOIs
StatePublished - Jan 31 2018

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Voltage-Gated Sodium Channels
Spinal Ganglia
Neuralgia
Paclitaxel
Peripheral Nervous System Diseases
Drug Therapy
Neurons
Calcitonin Gene-Related Peptide
NAV1.7 Voltage-Gated Sodium Channel
Action Potentials
Fluorescent Antibody Technique
Sodium Channel Blockers
Spinal Injections
Carisoprodol
Baths
Phenotype
Gene Expression
Pain
Therapeutics

Keywords

  • Cancer
  • Pain
  • Patch clamp
  • Spontaneous activity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Drg voltage-gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. / Li, Yan; North, Robert Y.; Rhines, Laurence D.; Tatsui, Claudio Esteves; Rao, Ganesh; Edwards, Denaya D.; Cassidy, Ryan M.; Harrison, Daniel S.; Johansson, Caj A.; Zhang, Hongmei; Dougherty, Patrick M.

In: Journal of Neuroscience, Vol. 38, No. 5, 31.01.2018, p. 1124-1136.

Research output: Contribution to journalArticle

Li, Yan ; North, Robert Y. ; Rhines, Laurence D. ; Tatsui, Claudio Esteves ; Rao, Ganesh ; Edwards, Denaya D. ; Cassidy, Ryan M. ; Harrison, Daniel S. ; Johansson, Caj A. ; Zhang, Hongmei ; Dougherty, Patrick M. / Drg voltage-gated sodium channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 5. pp. 1124-1136.
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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 (Nav1.7) 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 Nav1.7 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 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 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 Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.",
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AU - North, Robert Y.

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AU - Tatsui, Claudio Esteves

AU - Rao, Ganesh

AU - Edwards, Denaya D.

AU - Cassidy, Ryan M.

AU - Harrison, Daniel S.

AU - Johansson, Caj A.

AU - Zhang, Hongmei

AU - Dougherty, Patrick M.

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N2 - 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 (Nav1.7) 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 Nav1.7 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 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 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 Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.

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