title: A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain.
abstract: Pathological pain is one of the most common neurological complications in patients with HIV-1/AIDS. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is upregulated in the spinal cord dorsal horn (SDH) of the patients with HIV who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly upregulates 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 Box-5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hind paw. 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 through 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 through JNK/TNF-α signaling.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA Hainan Provincial Institute for Drug Control, Haikou, Hainan, China Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skane University Hospital, Malmo, Sweden.
authors.forename: Su-Bo
authors.initials: SB
authors.lastname: Yuan
authors.forename: Guangchen
authors.initials: G
authors.lastname: Ji
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
authors.forename: Volker
authors.initials: V
authors.lastname: Neugebauer
authors.forename: Shao-Jun
authors.initials: SJ
authors.lastname: Tang
mesh_terms: D000818:Animals; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000633:toxicity*; D007278:Injections, Spinal; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051153:Wnt Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D015699:HIV Envelope Protein gp120; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C514793:gp120 protein, Human immunodeficiency virus 1
references.citation: J Neurosci. 2008 May 7;28(19):5072-81
references.pmid: 18463260
references.citation: Nat Rev Neurosci. 2005 May;6(5):351-62
references.pmid: 15832199
references.citation: J Neurosci. 2009 Jan 7;29(1):159-68
references.pmid: 19129394
references.citation: J Neurosci. 2013 Apr 10;33(15):6540-51
references.pmid: 23575851
references.citation: J Neurophysiol. 1999 Jul;82(1):272-82
references.pmid: 10400956
references.citation: Pain Physician. 2014 Jan-Feb;17(1):E27-44
references.pmid: 24452656
references.citation: Neuron. 2014 Jul 2;83(1):104-21
references.pmid: 24991956
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19473-8
references.pmid: 19901340
references.citation: Mol Pain. 2012 Jun 19;8:47
references.pmid: 22713358
references.citation: Mol Brain. 2012 Jan 04;5:1
references.pmid: 22217152
references.citation: J Neurosci. 2001 Apr 15;21(8):2808-19
references.pmid: 11306633
references.citation: Ann Neurol. 2014 Jun;75(6):837-50
references.pmid: 24633867
references.citation: Gene Ther. 2014 Mar;21(3):328-36
references.pmid: 24451118
references.citation: J Assoc Nurses AIDS Care. 2010 Mar-Apr;21(2):125-33
references.pmid: 20116299
references.citation: J Neurosci. 2006 Oct 4;26(40):10299-304
references.pmid: 17021185
references.citation: J Biol Chem. 2013 May 10;288(19):13610-9
references.pmid: 23539626
references.citation: J Neurosci. 2001 Jul 15;21(14):5027-35
references.pmid: 11438578
references.citation: Pain. 2007 Dec 15;133(1-3):47-63
references.pmid: 17433546
references.citation: Mol Pain. 2011 May 20;7:40
references.pmid: 21599974
references.citation: J Biol Chem. 2006 Apr 28;281(17):11910-6
references.pmid: 16501258
references.citation: Neurodegener Dis. 2012;10(1-4):23-6
references.pmid: 22261402
references.citation: Pain. 1997 Apr;70(2-3):117-23
references.pmid: 9150284
references.citation: J Neuroinflammation. 2010 Apr 16;7:27
references.pmid: 20398373
references.citation: J Pain. 2008 Feb;9(2):174-84
references.pmid: 18088557
references.citation: J Neurosci. 2012 Mar 14;32(11):3910-6
references.pmid: 22423111
references.citation: Pain Physician. 2011 Nov-Dec;14(6):E505-24
references.pmid: 22086103
references.citation: Biochim Biophys Acta. 2004 Mar 11;1697(1-2):89-101
references.pmid: 15023353
references.citation: J Neurosci. 2012 Aug 8;32(32):10833-40
references.pmid: 22875918
references.citation: Annu Rev Cell Dev Biol. 2004;20:781-810
references.pmid: 15473860
references.citation: Int J Neurosci. 2015 Feb;125(2):147-53
references.pmid: 24738716
references.citation: Med Care. 2004 Feb;42(2):129-38
references.pmid: 14734950
references.citation: Neurosci Lett. 2008 Jun 6;437(3):180-3
references.pmid: 18455869
references.citation: Eur J Pharmacol. 1980 Oct 17;67(2-3):313-6
references.pmid: 6893963
references.citation: J Biol Chem. 2006 Feb 3;281(5):2740-9
references.pmid: 16330545
references.citation: Neurology. 2005 Mar 8;64(5):842-8
references.pmid: 15753420
references.citation: J Neuroimmune Pharmacol. 2012 Dec;7(4):904-13
references.pmid: 22547300
references.citation: J Clin Invest. 2013 May;123(5):2268-86
references.pmid: 23585476
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):77-86
references.pmid: 20010950
references.citation: Science. 2009 Aug 7;325(5941):760-4
references.pmid: 19661434
references.citation: J Pain Res. 2011;4:331-45
references.pmid: 22090802
references.citation: J Neurosci. 2009 Apr 1;29(13):4096-108
references.pmid: 19339605
references.citation: Health Technol Assess. 2006 Nov;10(42):iii-iv, xi-xiii, 1-229
references.pmid: 17049139
references.citation: J Neuroimmunol. 2001 May 1;116(1):29-39
references.pmid: 11311327
references.citation: Brain Res. 2000 Apr 7;861(1):105-16
references.pmid: 10751570
references.citation: Neurosci Res. 2014 Feb;79:34-40
references.pmid: 24361264
references.citation: J Neuroimmune Pharmacol. 2013 Sep;8(4):956-64
references.pmid: 23737037