Skip to main content

Advertisement

SpringerLink
Log in

Wnt Signaling in the Pathogenesis of Human HIV-Associated Pain Syndromes

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Many synaptic plasticity-related signaling pathways have been identified as important regulators of the pathogenesis of chronic pain in animal models. However, their relevance to human pathological pain is rarely confirmed rigorously. Recent studies suggest that Wnt signaling plays critical roles in synaptic plasticity and is dysregulated in the spinal cord dorsal horn (SDH) of different mouse pain models. In this study, we compared the protein levels of Wnt ligands, Wnt receptors and their downstream effector proteins in the SDH from non-HIV patients, HIV patients who developed chronic pain (‘pain-positive’ HIV patients), and HIV patients who did not develop chronic pain (‘pain-negative’ HIV patients). Our results indicate that many Wnt ligands and downstream effector proteins were specifically up-regulated in the SDH of ‘pain-positive’ HIV patients but not in the ‘pain-negative’ HIV patients. These findings describe an HIV pain-associated activation of Wnt signaling in the SDH of human patients. Given the established role of Wnt signaling in the regulation of synaptic plasticity, these results suggest that the activated Wnt signaling might contribute to the expression of the synaptic plasticity in the SDH during the pathogenesis of HIV-associated chronic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ahmad-Annuar A, Ciani L, Simeonidis I, Herreros J, Fredj NB, Rosso SB, Hall A, Brickley S, Salinas PC (2006) Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release. J Cell Biol 174:127–139

    Article  PubMed  CAS  Google Scholar 

  • Ataman B, Ashley J, Gorczyca M, Ramachandran P, Fouquet W, Sigrist SJ, Budnik V (2008) Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling. Neuron 57:705–718

    Article  PubMed  CAS  Google Scholar 

  • Avila ME, Sepulveda FJ, Burgos CF, Moraga-Cid G, Parodi J, Moon RT, Aguayo LG, Opazo C, De Ferrari GV (2010) Canonical Wnt3a modulates intracellular calcium and enhances excitatory neurotransmission in hippocampal neurons. J Biol Chem 285:18939–18947

    Article  PubMed  CAS  Google Scholar 

  • Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

    Article  PubMed  CAS  Google Scholar 

  • Beaumont V, Thompson SA, Choudhry F, Nuthall H, Glantschnig H, Lipfert L, David GR, Swain CJ, McAllister G, Munoz-Sanjuan I (2007) Evidence for an enhancement of excitatory transmission in adult CNS by Wnt signaling pathway modulation. Mol Cell Neurosci 35:513–524

    Article  PubMed  CAS  Google Scholar 

  • Camilli TC, Weeraratna AT (2010) Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression. Biochem Pharmacol 80:702–711

    Article  PubMed  CAS  Google Scholar 

  • Catani MV, Corasaniti MT, Navarra M, Nistico G, Finazzi-Agro A, Melino G (2000) gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors. J Neurochem 74:2373–2379

    Article  PubMed  CAS  Google Scholar 

  • Cerpa W, Gambrill A, Inestrosa NC, Barria A (2011) Regulation of NMDA-receptor synaptic transmission by Wnt signaling. J Neurosci 31:9466–9471

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Park CS, Tang SJ (2006) Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J Biol Chem 281:11910–11916

    Article  PubMed  CAS  Google Scholar 

  • Christman MA 2nd, Goetz DJ, Dickerson E, McCall KD, Lewis CJ, Benencia F, Silver MJ, Kohn LD, Malgor R (2008) Wnt5a is expressed in murine and human atherosclerotic lesions. Am J Physiol Heart Circ Physiol 294:H2864–H2870

    Article  PubMed  CAS  Google Scholar 

  • Ciani L, Boyle KA, Dickins E, Sahores M, Anane D, Lopes DM, Gibb AJ, Salinas PC (2011) Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca(2)(+)/Calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A 108:10732–10737

    Article  PubMed  CAS  Google Scholar 

  • Dalakas MC (2001) Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 6:14–20

    Article  PubMed  CAS  Google Scholar 

  • Davis EK, Zou Y, Ghosh A (2008) Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Dev 3:32

    Article  PubMed  Google Scholar 

  • Evers S, Wibbeke B, Reichelt D, Suhr B, Brilla R, Husstedt I (2000) The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses. Pain 85:191–200

    Article  PubMed  CAS  Google Scholar 

  • Farias GG, Alfaro IE, Cerpa W, Grabowski CP, Godoy JA, Bonansco C, Inestrosa NC (2009) Wnt-5a/JNK signaling promotes the clustering of PSD-95 in hippocampal neurons. J Biol Chem 284:15857–15866

    Article  PubMed  CAS  Google Scholar 

  • Gemignani A, Paudice P, Pittaluga A, Raiteri M (2000) The HIV-1 coat protein gp120 and some of its fragments potently activate native cerebral NMDA receptors mediating neuropeptide release. Eur J Neurosci 12:2839–2846

    Article  PubMed  CAS  Google Scholar 

  • Hewitt DJ, McDonald M, Portenoy RK, Rosenfeld B, Passik S, Breitbart W (1997) Pain syndromes and etiologies in ambulatory AIDS patients. Pain 70:117–123

    Article  PubMed  CAS  Google Scholar 

  • Ho HY, Susman MW, Bikoff JB, Ryu YK, Jonas AM, Hu L, Kuruvilla R, Greenberg ME (2012) Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci U S A 109:4044–4051

    PubMed  CAS  Google Scholar 

  • Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22:1172–1183

    Article  PubMed  CAS  Google Scholar 

  • Keswani SC, Jack C, Zhou C, Hoke A (2006) Establishment of a rodent model of HIV-associated sensory neuropathy. J Neurosci 26:10299–10304

    Article  PubMed  CAS  Google Scholar 

  • Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16:1258–1266

    Article  PubMed  CAS  Google Scholar 

  • Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926

    Article  PubMed  Google Scholar 

  • Li B, Zhong L, Yang X, Andersson T, Huang M, Tang SJ (2011) WNT5A signaling contributes to Abeta-induced neuroinflammation and neurotoxicity. PLoS One 6:e22920

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Li B, Wan X, Zhang W, Zhong L, Tang SJ (2012) NMDA receptor activation stimulates transcription-independent rapid wnt5a protein synthesis via the MAPK signaling pathway. Mol Brain 5:1

    Article  PubMed  Google Scholar 

  • Li B, Shi Y, Shu J, Gao J, Wu P, Tang SJ (2013) Wingless-type mammary tumor virus integration site family, member 5A (Wnt5a) regulates human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120)-induced expression of pro-inflammatory cytokines via the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK) signaling pathways. J Biol Chem 288:13610–13619

    Google Scholar 

  • Liu JX, Pinnock SB, Herbert J (2011) Novel control by the CA3 region of the hippocampus on neurogenesis in the dentate gyrus of the adult rat. PLoS One 6:e17562

    Article  PubMed  CAS  Google Scholar 

  • Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810

    Article  PubMed  CAS  Google Scholar 

  • Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J (2002) Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22:1184–1193

    Article  PubMed  CAS  Google Scholar 

  • Maguschak KA, Ressler KJ (2008) Beta-catenin is required for memory consolidation. Nat Neurosci 11:1319–1326

    Article  PubMed  CAS  Google Scholar 

  • Maguschak KA, Ressler KJ (2011) Wnt signaling in amygdala-dependent learning and memory. J Neurosci 31:13057–13067

    Article  PubMed  CAS  Google Scholar 

  • Melli G, Keswani SC, Fischer A, Chen W, Hoke A (2006) Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy. Brain 129:1330–1338

    Article  PubMed  Google Scholar 

  • Melzack R, Coderre TJ, Katz J, Vaccarino AL (2001) Central neuroplasticity and pathological pain. Ann N Y Acad Sci 933:157–174

    Article  PubMed  CAS  Google Scholar 

  • Mikels A, Minami Y, Nusse R (2009) Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling. J Biol Chem 284:30167–30176

    Article  PubMed  CAS  Google Scholar 

  • Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  PubMed  CAS  Google Scholar 

  • Mirsattari SM, Power C, Nath A (1999) Primary headaches in HIV-infected patients. Headache 39:3–10

    Article  PubMed  CAS  Google Scholar 

  • Morgello S, Gelman BB, Kozlowski PB, Vinters HV, Masliah E, Cornford M, Cavert W, Marra C, Grant I, Singer EJ (2001) The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease. Neuropathol Appl Neurobiol 27:326–335

    Article  PubMed  CAS  Google Scholar 

  • Morgello S, Estanislao L, Simpson D, Geraci A, DiRocco A, Gerits P, Ryan E, Yakoushina T, Khan S, Mahboob R, Naseer M, Dorfman D, Sharp V, Manhattan HIVBB (2004) HIV-associated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: the Manhattan HIV Brain Bank. Arch Neurol 61:546–551

    Article  PubMed  Google Scholar 

  • Neuberger J (2013) Transplantation: assessment of liver allograft steatosis. Nat Rev Gastroenterol Hepatol 283:5918–5927

    Google Scholar 

  • Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ (2001) Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 21:5027–5035

    PubMed  CAS  Google Scholar 

  • Pereira C, Schaer DJ, Bachli EB, Kurrer MO, Schoedon G (2008) Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 28:504–510

    Article  PubMed  CAS  Google Scholar 

  • Polydefkis M, Yiannoutsos CT, Cohen BA, Hollander H, Schifitto G, Clifford DB, Simpson DM, Katzenstein D, Shriver S, Hauer P, Brown A, Haidich AB, Moo L, McArthur JC (2002) Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 58:115–119

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V, Rutkowski MD, DeLeo JA (2002) The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J Neurosci 22:9980–9989

    PubMed  CAS  Google Scholar 

  • Rygh LJ, Svendsen F, Hole K, Tjolsen A (1999) Natural noxious stimulation can induce long-term increase of spinal nociceptive responses. Pain 82:305–310

    Article  PubMed  CAS  Google Scholar 

  • Sandkuhler J, Liu X (1998) Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci 10:2476–2480

    Article  PubMed  CAS  Google Scholar 

  • Schmeisser MJ, Grabrucker AM, Bockmann J, Boeckers TM (2009) Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses. J Biol Chem 284:29146–29157

    Article  PubMed  CAS  Google Scholar 

  • Sen M, Lauterbach K, El-Gabalawy H, Firestein GS, Corr M, Carson DA (2000) Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A 97:2791–2796

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Gelman BB, Lisinicchia JG, Tang SJ (2012a) Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J Neurosci 32:10833–10840

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Yuan S, Li B, Wang J, Carlton SM, Chung K, Chung JM, Tang SJ (2012b) Regulation of Wnt signaling by nociceptive input in animal models. Mol Pain 8:47

    Article  PubMed  CAS  Google Scholar 

  • Simpson DM, Kitch D, Evans SR, McArthur JC, Asmuth DM, Cohen B, Goodkin K, Gerschenson M, So Y, Marra CM, Diaz-Arrastia R, Shriver S, Millar L, Clifford DB, Group AAS (2006) HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology 66:1679–1687

    Article  PubMed  CAS  Google Scholar 

  • Speese SD, Budnik V (2007) Wnts: up-and-coming at the synapse. Trends Neurosci 30:268–275

    Article  PubMed  CAS  Google Scholar 

  • Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, Krueger JG (2011) Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol 131:391–400

    Article  PubMed  CAS  Google Scholar 

  • Tang SJ (2007) The synaptic Wnt signaling hypothesis. Synapse 61:866–868

    Article  PubMed  CAS  Google Scholar 

  • Varela-Nallar L, Alfaro IE, Serrano FG, Parodi J, Inestrosa NC (2010) Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses. Proc Natl Acad Sci U S A 107:21164–21169

    Article  PubMed  CAS  Google Scholar 

  • Verma S, Estanislao L, Simpson D (2005) HIV-associated neuropathic pain: epidemiology, pathophysiology and management. CNS Drugs 19:325–334

    Article  PubMed  Google Scholar 

  • Wallace VC, Blackbeard J, Pheby T, Segerdahl AR, Davies M, Hasnie F, Hall S, McMahon SB, Rice AS (2007) Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 133:47–63

    Article  PubMed  CAS  Google Scholar 

  • Wan XZ, Li B, Li YC, Yang XL, Zhang W, Zhong L, Tang SJ (2012) Activation of NMDA receptors upregulates a disintegrin and metalloproteinase 10 via a Wnt/MAPK signaling pathway. J Neurosci 32:3910–3916

    Article  PubMed  CAS  Google Scholar 

  • Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–S15

    Article  PubMed  Google Scholar 

  • Yuan S, Shi Y, Tang SJ (2012) Wnt signaling in the pathogenesis of multiple sclerosis-associated chronic pain. J NeuroImmune Pharm 7:904–913

    Article  Google Scholar 

  • Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ (2013) WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest 123:2268–2286

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the UTMB start-up funds, the Whitehall Foundation and National Institutes of Health Grants R01-NS079166 to SJT, NIH Grants U01-MH-083507 and R24-NS-045491 to BBG, and Zhejiang Natural Science Foundation LY13H090015 to JS.

Conflict of interest disclosure

There is no conflict of interest for the authors.

Author information

Authors and Affiliations

  1. Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, 77555-1069, USA

    Yuqiang Shi, Jianhong Shu, Benjamin B. Gelman & Shao-Jun Tang

  2. Institute of Biochemistry, Zhejiang Sci-Tech University, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Hangzhou, 310018, China

    Jianhong Shu

  3. Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA

    Benjamin B. Gelman & Joshua G. Lisinicchia

Authors
  1. Yuqiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianhong Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benjamin B. Gelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joshua G. Lisinicchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shao-Jun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shao-Jun Tang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, Y., Shu, J., Gelman, B.B. et al. Wnt Signaling in the Pathogenesis of Human HIV-Associated Pain Syndromes. J Neuroimmune Pharmacol 8, 956–964 (2013). https://doi.org/10.1007/s11481-013-9474-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-013-9474-4

Keywords

Search

Navigation