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A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain.

Yuan, Subo; Ji, Guangchen; Li, Bei; Andersson, Tommy LU ; Neugebauer, Volker and Tang, Shao-Jun (2015) In Pain 156(7). p.1311-1319
Abstract
Pathological pain is one of the most common neurological complications in HIV-1/AIDS patients. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is up-regulated in the spinal dorsal horn (SDH) of the HIV patients who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly up-regulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-α pathway. We observed that the JNK-specific inhibitor SP600125... (More)
Pathological pain is one of the most common neurological complications in HIV-1/AIDS patients. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is up-regulated in the spinal dorsal horn (SDH) of the HIV patients who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly up-regulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-α pathway. We observed that the JNK-specific inhibitor SP600125 blocked either gp120- or Foxy5-induced allodynia. Similarly, the TNF-α-specific antagonist Enbrel also reversed either gp120- or Foxy5-induced allodynia. These data suggest that JNK and TNF-α mediate the biological effects of Wnt5a in regulating gp120-induced allodynia. To investigate the cellular mechanism, we performed extracellular single-unit recording from SDH neurons in anesthetized mice. Both Box5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hindpaw. Furthermore, while Foxy5 potentiated spike frequency of SDH neurons, either SP600125 or Enbrel blocked the potentiation. The data indicate that Wnt5a potentiates the activity of SDH neurons via the JNK-TNF-α pathway. Collectively, our findings suggest that Wnt5a regulates the pathogenesis of gp120-induced pain, likely by sensitizing pain-processing SDH neurons via JNK/TNF-α signaling. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pain
volume
156
issue
7
pages
1311 - 1319
publisher
Elsevier
external identifiers
  • pmid:25840108
  • wos:000357426200018
  • scopus:84945304556
ISSN
1872-6623
DOI
10.1097/j.pain.0000000000000177
language
English
LU publication?
yes
id
7d52b122-391d-4243-8f70-1009bfc59098 (old id 5345593)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25840108?dopt=Abstract
date added to LUP
2015-05-06 19:47:00
date last changed
2017-10-22 03:15:57
@article{7d52b122-391d-4243-8f70-1009bfc59098,
  abstract     = {Pathological pain is one of the most common neurological complications in HIV-1/AIDS patients. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is up-regulated in the spinal dorsal horn (SDH) of the HIV patients who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly up-regulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-α pathway. We observed that the JNK-specific inhibitor SP600125 blocked either gp120- or Foxy5-induced allodynia. Similarly, the TNF-α-specific antagonist Enbrel also reversed either gp120- or Foxy5-induced allodynia. These data suggest that JNK and TNF-α mediate the biological effects of Wnt5a in regulating gp120-induced allodynia. To investigate the cellular mechanism, we performed extracellular single-unit recording from SDH neurons in anesthetized mice. Both Box5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hindpaw. Furthermore, while Foxy5 potentiated spike frequency of SDH neurons, either SP600125 or Enbrel blocked the potentiation. The data indicate that Wnt5a potentiates the activity of SDH neurons via the JNK-TNF-α pathway. Collectively, our findings suggest that Wnt5a regulates the pathogenesis of gp120-induced pain, likely by sensitizing pain-processing SDH neurons via JNK/TNF-α signaling.},
  author       = {Yuan, Subo and Ji, Guangchen and Li, Bei and Andersson, Tommy and Neugebauer, Volker and Tang, Shao-Jun},
  issn         = {1872-6623},
  language     = {eng},
  number       = {7},
  pages        = {1311--1319},
  publisher    = {Elsevier},
  series       = {Pain},
  title        = {A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain.},
  url          = {http://dx.doi.org/10.1097/j.pain.0000000000000177},
  volume       = {156},
  year         = {2015},
}