Activation of TLR-4 to produce tumour necrosis factor-α in neuropathic pain caused by paclitaxel.

Abstract

BACKGROUND:

Neuropathic pain is a common complication of treatment with the anti-neoplastic drug paclitaxel. Animal studies suggest neuroinflammation and transient receptor potential channels TRPA1 and TRPV4 are involved in the pathogenesis of pain in this condition. However, how neuroinflammation and TRPA1 and TRPV4 are linked to cause pain in paclitaxel-treated animals is not known.

METHODS:

Paclitaxel-induced pain was modelled by IP injection of paclitaxel (16 mg/kg) once a week for 5 weeks. The role of toll-like receptor 4 (TLR-4) in tumour necrosis factor-α (TNF-α) production and the effect of TNF-α on the expression of TRPA1 and TRPV4 were evaluated in vitro and in vivo. TNF-α signalling in dorsal root ganglion (DRG) was blocked by expressing soluble TNF receptor I (TNFsR) from a herpes simplex virus (HSV)-based vector (vTNFsR).

RESULTS:

Paclitaxel treatment increased the expression and release of TNF-α in satellite glial cells and increased the expression of TRPA1 and TRPV4 in DRG neurons in animals. In vitro, paclitaxel enhanced the expression and release of TNF-α in enriched primary satellite glial cells, an effect that was blocked by an inhibitor of TLR-4. Direct application of TNF-α to primary DRG neurons in culture up-regulated the expression of TRPA1 and TRPV4. In vivo, vector-mediated TNFsR release from DRG neurons reduced paclitaxel-induced up-regulation of TRPA1 and TRPV4 expression and prevented paclitaxel-induced pain.

CONCLUSION:

These results suggest that paclitaxel activation of TLR-4 to cause release of TNF-α from satellite glial cells increases the expression of TRPA1 and TRPV4 in DRG neurons to cause neuropathic pain.

• Authors: Z Wu, S Wang, I Wu, M Mata, D J Fink
• Journal: European journal of pain (London, England) (Eur J Pain) Vol. 19 Issue 7 Pg. 889-98 (Aug 2015) ISSN: 1532-2149 [Electronic] England
• PMID: 25388329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 European Pain Federation - EFIC®

Chemical References

• Antineoplastic Agents, Phytogenic
• TRPA1 Cation Channel
• TRPC Cation Channels
• TRPV Cation Channels
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Trpa1 protein, rat
• Trpv4 protein, rat
• Tumor Necrosis Factor-alpha
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (adverse effects)
• Behavior, Animal (drug effects)
• Ganglia, Spinal (drug effects)
• Male
• Neuralgia (chemically induced, psychology)
• Neuroglia (drug effects)
• Paclitaxel (adverse effects)
• Primary Cell Culture
• Rats
• Rats, Sprague-Dawley
• Satellite Cells, Perineuronal (metabolism)
• TRPA1 Cation Channel
• TRPC Cation Channels (biosynthesis, genetics)
• TRPV Cation Channels (biosynthesis, genetics)
• Toll-Like Receptor 4 (antagonists & inhibitors, genetics, metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis, pharmacology)
• Up-Regulation (drug effects)