Advertisement

Molecular Neurobiology

, Volume 55, Issue 5, pp 3959–3975 | Cite as

Drug-Induced HSP90 Inhibition Alleviates Pain in Monoarthritic Rats and Alters the Expression of New Putative Pain Players at the DRG

  • Diana Sofia Marques Nascimento
  • Catarina Soares Potes
  • Miguel Luz Soares
  • António Carlos Ferreira
  • Marzia Malcangio
  • José Manuel Castro-Lopes
  • Fani Lourença Moreira Neto
Article

Abstract

Purinergic receptors (P2XRs) have been widely associated with pain states mostly due to their involvement in neuron–glia communication. Interestingly, we have previously shown that satellite glial cells (SGC), surrounding dorsal root ganglia (DRG) neurons, become activated and proliferate during monoarthritis (MA) in the rat. Here, we demonstrate that P2X7R expression increases in ipsilateral DRG after 1 week of disease, while P2X3R immunoreactivity decreases. We have also reported a significant induction of the activating transcriptional factor 3 (ATF3) in MA. In this study, we show that ATF3 knocked down in DRG cell cultures does not affect the expression of P2X7R, P2X3R, or glial fibrillary acidic protein (GFAP). We suggest that P2X7R negatively regulates P2X3R, which, however, is unlikely mediated by ATF3. Interestingly, we found that ATF3 knockdown in vitro induced significant decreases in the heat shock protein 90 (HSP90) expression. Thus, we evaluated in vivo the involvement of HSP90 in MA and demonstrated that the HSP90 messenger RNA levels increase in ipsilateral DRG of inflamed animals. We also show that HSP90 is mostly found in a cleaved form in this condition. Moreover, administration of a HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), attenuated MA-induced mechanical allodynia in the first hours. The drug also reversed the HSP90 upregulation and cleavage. 17-DMAG seemed to attenuate glial activation and neuronal sensitization (as inferred by downregulation of GFAP and P2X3R in ipsilateral DRG) which might correlate with the observed pain alleviation. Our data indicate a role of HSP90 in MA pathophysiology, but further investigation is necessary to clarify the underlying mechanisms.

Keywords

Joint inflammatory pain DRG neurons ATF3 P2X receptors SGC activation HSP90 inhibition 

Notes

Acknowledgements

The study was supported by the Chair on Pain Medicine of the Faculty of Medicine, University of Porto and by the Grünenthal Foundation—Portugal. The first author DSMN received a doctoral grant (SFRH/BD/79497/2011) by Fundação para a Ciência e a Tecnologia (FCT), Portugal. CSP was also supported by a post-doctoral grant (SFRH/BPD/87537/2012) from FCT. The authors would also like to thank José Pedro Castro (from Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke; Germany) and Francisco Nóvoa Faria (from Dept. Fisiologia e Cirurgia Cardiotorácica, CIM-FMUP) for their help and expertise concerning HSP90 fluorescent detection using LI-COR system.

Compliance with Ethical Standards

The experiments were authorized by the animal welfare body (ORBEA) of the Faculty of Medicine of the University of Porto. Procedures were carried out according to the European Communities Council Directive of September 22, 2010 (2010/63/EC), the ethical guidelines for investigation of experimental pain in animals [29] and the “Principles of laboratory animal care” (NIH publication no. 86-23, revised 1985).

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Vallejo R, Tilley DM, Vogel L, Benyamin R (2010) The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract 10(3):167–184CrossRefPubMedGoogle Scholar
  2. 2.
    Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2(12):973–985CrossRefPubMedGoogle Scholar
  4. 4.
    Costa FA, Moreira Neto FL (2015) Satellite glial cells in sensory ganglia: its role in pain. Rev Bras Anestesiol 65(1):73–81CrossRefPubMedGoogle Scholar
  5. 5.
    Jasmin L, Vit JP, Bhargava A, Ohara PT (2010) Can satellite glial cells be therapeutic targets for pain control? Neuron Glia Biol 6(1):63–71CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nascimento DS, Castro-Lopes JM, Moreira Neto FL (2014) Satellite glial cells surrounding primary afferent neurons are activated and proliferate during monoarthritis in rats: is there a role for ATF3? PLoS One 9(9):e108152CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Habermacher C, Dunning K, Chataigneau T, Grutter T (2015) Molecular structure and function of P2X receptors. Neuropharmacology 104:18–30CrossRefPubMedGoogle Scholar
  8. 8.
    Chizh BA, Illes P (2001) P2X receptors and nociception. Pharmacol Rev 53(4):553–568PubMedGoogle Scholar
  9. 9.
    Alves LA, Bezerra RJ, Faria RX, Ferreira LG, da Silva FV (2013) Physiological roles and potential therapeutic applications of the P2X7 receptor in inflammation and pain. Molecules 18(9):10953–10972CrossRefPubMedGoogle Scholar
  10. 10.
    Dunn PM, Zhong Y, Burnstock G (2001) P2X receptors in peripheral neurons. Prog Neurobiol 65(2):107–134CrossRefPubMedGoogle Scholar
  11. 11.
    Prado FC, Araldi D, Vieira AS, Oliveira-Fusaro MC, Tambeli CH, Parada CA (2013) Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. Neuropharmacology 67:252–258CrossRefPubMedGoogle Scholar
  12. 12.
    Wirkner K, Sperlagh B, Illes P (2007) P2X3 receptor involvement in pain states. Mol Neurobiol 36(2):165–183CrossRefPubMedGoogle Scholar
  13. 13.
    Elson K, Simmons A, Speck P (2004) Satellite cell proliferation in murine sensory ganglia in response to scarification of the skin. Glia 45(1):105–109CrossRefPubMedGoogle Scholar
  14. 14.
    Madrigal-Matute J, Lopez-Franco O, Blanco-Colio LM, Munoz-Garcia B, Ramos-Mozo P, Ortega L, Egido J, Martin-Ventura JL (2010) Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc Res 86(2):330–337CrossRefPubMedGoogle Scholar
  15. 15.
    Qi J, Han X, Liu HT, Chen T, Zhang JL, Yang P, Bo SH, Lu XT et al (2014) 17-Dimethylaminoethylamino-17-demethoxygeldanamycin attenuates inflammatory responses in experimental stroke. Biol Pharm Bull 37(11):1713–1718Google Scholar
  16. 16.
    Rice JW, Veal JM, Fadden RP, Barabasz AF, Partridge JM, Barta TE, Dubois LG, Huang KH et al (2008) Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum 58(12):3765–3775Google Scholar
  17. 17.
    Adinolfi E, Kim M, Young MT, Di Virgilio F, Surprenant A (2003) Tyrosine phosphorylation of HSP90 within the P2X7 receptor complex negatively regulates P2X7 receptors. J Biol Chem 278(39):37344–37351CrossRefPubMedGoogle Scholar
  18. 18.
    Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y et al (2002) Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 16(6):601–603Google Scholar
  19. 19.
    Lisi L, McGuire S, Sharp A, Chiosis G, Navarra P, Feinstein DL, Dello Russo C (2013) The novel HSP90 inhibitor, PU-H71, suppresses glial cell activation but weakly affects clinical signs of EAE. J Neuroimmunol 255(1–2):1–7CrossRefPubMedGoogle Scholar
  20. 20.
    Urban MJ, Li C, Yu C, Lu Y, Krise JM, McIntosh MP, Rajewski RA, Blagg BS et al (2010) Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice. ASN Neuro 2(4):e00040Google Scholar
  21. 21.
    Tsan MF, Gao B (2004) Cytokine function of heat shock proteins. Am J Physiol Cell Physiol 286(4):C739–C744CrossRefPubMedGoogle Scholar
  22. 22.
    Hutchinson MR, Ramos KM, Loram LC, Wieseler J, Sholar PW, Kearney JJ, Lewis MT, Crysdale NY et al (2009) Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats. Neuroscience 164(4):1821–1832Google Scholar
  23. 23.
    Yun TJ, Harning EK, Giza K, Rabah D, Li P, Arndt JW, Luchetti D, Biamonte MA et al (2011) EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity. J Immunol 186(1):563–575Google Scholar
  24. 24.
    Hackl C, Lang SA, Moser C, Mori A, Fichtner-Feigl S, Hellerbrand C, Dietmeier W, Schlitt HJ et al (2010) Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition. BMC Cancer 10:668Google Scholar
  25. 25.
    Nascimento D, Pozza DH, Castro-Lopes JM, Neto FL (2011) Neuronal injury marker ATF-3 is induced in primary afferent neurons of monoarthritic rats. Neurosignals 19(4):210–221CrossRefPubMedGoogle Scholar
  26. 26.
    Lai PF, Cheng CF, Lin H, Tseng TL, Chen HH, Chen SH (2013) ATF3 protects against LPS-induced inflammation in mice via inhibiting HMGB1 expression. Evid Based Complement Alternat Med 2013:716481PubMedPubMedCentralGoogle Scholar
  27. 27.
    Suganami T, Yuan X, Shimoda Y, Uchio-Yamada K, Nakagawa N, Shirakawa I, Usami T, Tsukahara T et al (2009) Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue. Circ Res 105(1):25–32Google Scholar
  28. 28.
    Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BR (2007) Negative regulation of TLR-signaling pathways by activating transcription factor-3. J Immunol 179(6):3622–3630CrossRefPubMedGoogle Scholar
  29. 29.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16(2):109–110CrossRefPubMedGoogle Scholar
  30. 30.
    Butler SH, Godefroy F, Besson JM, Weil-Fugazza J (1992) A limited arthritic model for chronic pain studies in the rat. Pain 48(1):73–81CrossRefPubMedGoogle Scholar
  31. 31.
    Lourenco Neto F, Schadrack J, Platzer S, Zieglgansberger W, Tolle TR, Castro-Lopes JM (2000) Expression of metabotropic glutamate receptors mRNA in the thalamus and brainstem of monoarthritic rats. Brain Res Mol Brain Res 81(1–2):140–154CrossRefPubMedGoogle Scholar
  32. 32.
    Ossipov MH, Suarez LJ, Spaulding TC (1988) A comparison of the antinociceptive and behavioral effects of intrathecally administered opiates, alpha-2-adrenergic agonists, and local anesthetics in mice and rats. Anesth Analg 67(7):616–624CrossRefPubMedGoogle Scholar
  33. 33.
    De la Calle JL, Paino CL (2002) A procedure for direct lumbar puncture in rats. Brain Res Bull 59(3):245–250CrossRefPubMedGoogle Scholar
  34. 34.
    Borges G, Neto F, Mico JA, Berrocoso E (2014) Reversal of monoarthritis-induced affective disorders by diclofenac in rats. Anesthesiology 120(6):1476–1490CrossRefPubMedGoogle Scholar
  35. 35.
    Cruz CD, Neto FL, Castro-Lopes J, McMahon SB, Cruz F (2005) Inhibition of ERK phosphorylation decreases nociceptive behaviour in monoarthritic rats. Pain 116(3):411–419CrossRefPubMedGoogle Scholar
  36. 36.
    Neto FL, Castro-Lopes JM (2000) Antinociceptive effect of a group II metabotropic glutamate receptor antagonist in the thalamus of monoarthritic rats. Neurosci Lett 296(1):25–28CrossRefPubMedGoogle Scholar
  37. 37.
    Pozza DH, Potes CS, Barroso PA, Azevedo L, Castro-Lopes JM, Neto FL (2010) Nociceptive behaviour upon modulation of mu-opioid receptors in the ventrobasal complex of the thalamus of rats. Pain 148(3):492–502CrossRefPubMedGoogle Scholar
  38. 38.
    Egorin MJ, Lagattuta TF, Hamburger DR, Covey JM, White KD, Musser SM, Eiseman JL (2002) Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 49(1):7–19CrossRefPubMedGoogle Scholar
  39. 39.
    Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM, Egorin MJ (2005) Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol 55(1):21–32CrossRefPubMedGoogle Scholar
  40. 40.
    Butler S, Weil-Fugazza J (1994) The foot-bend procedure as test of nociception for chronic studies in a model of monoarthritis in the rat. Pharmacol Commun 4:327–334Google Scholar
  41. 41.
    Delree P, Leprince P, Schoenen J, Moonen G (1989) Purification and culture of adult rat dorsal root ganglia neurons. J Neurosci Res 23(2):198–206CrossRefPubMedGoogle Scholar
  42. 42.
    Tse KH, Chow KB, Leung WK, Wong YH, Wise H (2014) Primary sensory neurons regulate Toll-like receptor-4-dependent activity of glial cells in dorsal root ganglia. Neuroscience 279:10–22CrossRefPubMedGoogle Scholar
  43. 43.
    Schmutzler BS, Roy S, Pittman SK, Meadows RM, Hingtgen CM (2011) Ret-dependent and Ret-independent mechanisms of Gfl-induced sensitization. Mol Pain 7:22CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Castro-Lopes JM, Tavares I, Tolle TR, Coito A, Coimbra A (1992) Increase in GABAergic cells and GABA levels in the spinal cord in unilateral inflammation of the hindlimb in the rat. Eur J Neurosci 4(4):296–301CrossRefPubMedGoogle Scholar
  45. 45.
    Ferreira-Gomes J, Neto FL, Castro-Lopes JM (2004) Differential expression of GABA(B(1b)) receptor mRNA in the thalamus of normal and monoarthritic animals. Biochem Pharmacol 68(8):1603–1611CrossRefPubMedGoogle Scholar
  46. 46.
    Potes CS, Neto FL, Castro-Lopes JM (2006) Administration of baclofen, a gamma-aminobutyric acid type B agonist in the thalamic ventrobasal complex, attenuates allodynia in monoarthritic rats subjected to the ankle-bend test. J Neurosci Res 83(3):515–523CrossRefPubMedGoogle Scholar
  47. 47.
    Sanchez-Nogueiro J, Marin-Garcia P, Miras-Portugal MT (2005) Characterization of a functional P2X(7)-like receptor in cerebellar granule neurons from P2X(7) knockout mice. FEBS Lett 579(17):3783–3788CrossRefPubMedGoogle Scholar
  48. 48.
    Stojilkovic SS, Leiva-Salcedo E, Rokic MB, Coddou C (2014) Regulation of ATP-gated P2X channels: from redox signaling to interactions with other proteins. Antioxid Redox Signal 21(6):953–970CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Beck R, Dejeans N, Glorieux C, Creton M, Delaive E, Dieu M, Raes M, Leveque P et al (2012) Hsp90 is cleaved by reactive oxygen species at a highly conserved N-terminal amino acid motif. PLoS One 7(7):e40795Google Scholar
  50. 50.
    Antonioli L, Giron MC, Colucci R, Pellegrini C, Sacco D, Caputi V, Orso G, Tuccori M et al (2014) Involvement of the P2X7 purinergic receptor in colonic motor dysfunction associated with bowel inflammation in rats. PLoS One 9(12):e116253Google Scholar
  51. 51.
    Chen Y, Zhang X, Wang C, Li G, Gu Y, Huang LY (2008) Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons. Proc Natl Acad Sci U S A 105(43):16773–16778CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Liu S, Shi Q, Zhu Q, Zou T, Li G, Huang A, Wu B, Peng L et al (2015) P2X(7) receptor of rat dorsal root ganglia is involved in the effect of moxibustion on visceral hyperalgesia. Purinergic Signal 11(2):161–169Google Scholar
  53. 53.
    North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4):1013–1067CrossRefPubMedGoogle Scholar
  54. 54.
    Cheng CF, Cheng JK, Chen CY, Lien CC, Chu D, Wang SY, Tsaur ML (2014) Mirror-image pain is mediated by nerve growth factor produced from tumor necrosis factor alpha-activated satellite glia after peripheral nerve injury. Pain 155(5):906–920CrossRefPubMedGoogle Scholar
  55. 55.
    Kage K, Niforatos W, Zhu CZ, Lynch KJ, Honore P, Jarvis MF (2002) Alteration of dorsal root ganglion P2X3 receptor expression and function following spinal nerve ligation in the rat. Exp Brain Res 147(4):511–519CrossRefPubMedGoogle Scholar
  56. 56.
    Chen Y, Li G, Huang LY (2012) P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol Pain 8:9CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chen Y, Li G, Huang LY (2015) p38 MAPK mediates glial P2X7R-neuronal P2Y1R inhibitory control of P2X3R expression in dorsal root ganglion neurons. Mol Pain 11(1):68PubMedPubMedCentralGoogle Scholar
  58. 58.
    Tsuzuki K, Kondo E, Fukuoka T, Yi D, Tsujino H, Sakagami M, Noguchi K (2001) Differential regulation of P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91(3):351–360CrossRefPubMedGoogle Scholar
  59. 59.
    Hsieh YL, Chiang H, Lue JH, Hsieh ST (2012) P2X3-mediated peripheral sensitization of neuropathic pain in resiniferatoxin-induced neuropathy. Exp Neurol 235(1):316–325CrossRefPubMedGoogle Scholar
  60. 60.
    Wu JX, Xu MY, Miao XR, Lu ZJ, Yuan XM, Li XQ, Yu WF (2012) Functional up-regulation of P2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain. Eur J Pain 16(10):1378–1388CrossRefPubMedGoogle Scholar
  61. 61.
    Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12(4–5):256–268CrossRefPubMedGoogle Scholar
  62. 62.
    Arulkumaran N, Unwin RJ, Tam FW (2011) A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs 20(7):897–915CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Dell’Antonio G, Quattrini A, Dal Cin E, Fulgenzi A, Ferrero ME (2002) Antinociceptive effect of a new P(2Z)/P2X7 antagonist, oxidized ATP, in arthritic rats. Neurosci Lett 327(2):87–90CrossRefPubMedGoogle Scholar
  64. 64.
    Sato A, Nakama K, Watanabe H, Satake A, Yamamoto A, Omi T, Hiramoto A, Masutani M et al (2014) Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-2′-deoxyuridine. FEBS J 281(7):1892–1900Google Scholar
  65. 65.
    Sevin M, Girodon F, Garrido C, de Thonel A (2015) HSP90 and HSP70: Implication in inflammation processes and therapeutic approaches for myeloproliferative neoplasms. Mediat Inflamm 2015:970242CrossRefGoogle Scholar
  66. 66.
    Poulet B, Beier F (2016) Targeting oxidative stress to reduce osteoarthritis. Arthritis Res Ther 18(1):32CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Castro JP, Reeg S, Botelho V, Almeida H, Grune T (2014) HSP90 cleavage associates with oxidized proteins accumulation after oxidative stress. Free Radic Biol Med 75(Suppl 1):S24–S25CrossRefPubMedGoogle Scholar
  68. 68.
    Neckers L, Neckers K (2002) Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents. Expert Opin Emerg Drugs 7(2):277–288CrossRefPubMedGoogle Scholar
  69. 69.
    Nollen EA, Morimoto RI (2002) Chaperoning signaling pathways: molecular chaperones as stress-sensing ‘heat shock’ proteins. J Cell Sci 115(Pt 14):2809–2816PubMedGoogle Scholar
  70. 70.
    Gorska M, Popowska U, Sielicka-Dudzin A, Kuban-Jankowska A, Sawczuk W, Knap N, Cicero G, Wozniak F (2012) Geldanamycin and its derivatives as Hsp90 inhibitors. Front Biosci 17:2269–2277CrossRefGoogle Scholar
  71. 71.
    Wolfgang CD, Liang G, Okamoto Y, Allen AE, Hai T (2000) Transcriptional autorepression of the stress-inducible gene ATF3. J Biol Chem 275(22):16865–16870CrossRefPubMedGoogle Scholar
  72. 72.
    Zou J, Guo Y, Guettouche T, Smith DF, Voellmy R (1998) Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94(4):471–480CrossRefPubMedGoogle Scholar
  73. 73.
    Neef DW, Jaeger AM, Thiele DJ (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10(12):930–944CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Gilchrist M, Henderson WR Jr, Clark AE, Simmons RM, Ye X, Smith KD, Aderem A (2008) Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation. J Exp Med 205(10):2349–2357CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83(5):711–730CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    McDowell TS, Yukhananov RY (2002) HSP90 inhibitors alter capsaicin- and ATP-induced currents in rat dorsal root ganglion neurons. Neuroreport 13(4):437–441CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Diana Sofia Marques Nascimento
    • 1
    • 2
    • 3
  • Catarina Soares Potes
    • 1
    • 2
    • 3
  • Miguel Luz Soares
    • 1
    • 2
    • 3
    • 4
  • António Carlos Ferreira
    • 1
    • 2
    • 3
    • 4
  • Marzia Malcangio
    • 5
  • José Manuel Castro-Lopes
    • 1
    • 2
    • 3
  • Fani Lourença Moreira Neto
    • 1
    • 2
    • 3
  1. 1.Departamento de Biomedicina—Unidade de Biologia Experimental, Centro de Investigação Médica (CIM)Faculdade de Medicina da Universidade do PortoPortoPortugal
  2. 2.Pain GroupInstituto de Biologia Molecular e Celular (IBMC)PortoPortugal
  3. 3.Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  4. 4.Laboratório de Apoio à Investigação em Medicina Molecular (LAIMM)Faculdade de Medicina da Universidade do PortoPortoPortugal
  5. 5.Wolfson Centre for Age Related DiseasesKing’s College LondonLondonUK

Personalised recommendations