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


CONCLUSIONS
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.
Department of Neurology, University of Michigan, USA.|VA Ann Arbor Healthcare System, USA.
Z
Z
Wu
Department of Neurology, University of Michigan, USA.|VA Ann Arbor Healthcare System, USA.
S
S
Wang
Department of Neurology, University of Michigan, USA.|VA Ann Arbor Healthcare System, USA.
I
I
Wu
Department of Neurology, University of Michigan, USA.|VA Ann Arbor Healthcare System, USA.
M
M
Mata
Department of Neurology, University of Michigan, USA.|VA Ann Arbor Healthcare System, USA.
D J
DJ
Fink
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000523:psychology; D009457:Neuroglia / Q000187:drug effects; D017239:Paclitaxel / Q000009:adverse effects*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D027161:Satellite Cells, Perineuronal / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000096:biosynthesis / Q000235:genetics; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C480976:Trpa1 protein, rat; C486577:Trpv4 protein, rat; D014409:Tumor Necrosis Factor-alpha; D017239:Paclitaxel