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Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain

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Abstract

Peripheral nerve injury leads to the activation of spinal cord astrocytes, which contribute to maintaining neuropathic (NP) pain behavior. Fibroblast growth factor-2 (FGF-2), a neurotrophic and gliogenic factor, is upregulated by spinal cord astrocytes in response to ligation of spinal nerves L5 and L6 (spinal nerve ligation [SpNL]). To evaluate the contribution of spinal astroglial FGF-2 to mechanical allodynia following SpNL, neutralizing antibodies to FGF-2 were injected intrathecally. Administration of 18 µg of anti-FGF-2 antibodies attenuated mechanical allodynia at day 21 after SpNL and reduced FGF-2 and glial acidic fibrillary protein mRNA expression and immunoreactivity in the L5 spinal cord segment of rats with SpNL. These results suggest that endogenous astroglial FGF-2 contributes to maintaining NP tactile allodynia associated with reactivity of spinal cord astrocytes and that inhibition of spinal FGF-2 ameliorates NP pain signs.

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References

  • Armstrong R. C., Le T. Q., Frost E. E., Borke R. C., and Vana A. C. (2002) Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter. J. Neurosci. 22, 8574–8585.

    PubMed  CAS  Google Scholar 

  • Arrud J. L., Sweitzer S., Rutkowski M. D., and DeLeo J. A. (2000) Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain. Brain Res. 879, 216–225.

    Article  Google Scholar 

  • Avola R., Di Tullio M. A., Fisichella A., Tayebati S. K., and Tomassoni D. (2004) Glial fibrillary acidic protein and vimentin expression is regulated by glucocorticoids and neurotrophic factors in primary rat astroglial cultures. Clin. Exp. Hypertens. 26, 323–333.

    Article  PubMed  CAS  Google Scholar 

  • Chaplan S. R., Bach F. W., Pogrel J. W., Chung J.-M., and Yaksh T. L. (1994) Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63.

    Article  PubMed  CAS  Google Scholar 

  • Clarke W. E., Berry M., Smith C., Kent A., and Logan A. (2001) Coordination of fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-2 (FGF-2) trafficking to nuclei of reactive astrocytes around cerebral lesions in adult rats. Mol. Cell. Neurosci. 17, 17–30.

    Article  PubMed  CAS  Google Scholar 

  • Colburn R. W., Rickman A. J., and DeLeo J. A. (1999) The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp. Neurol. 157, 289–304.

    Article  PubMed  CAS  Google Scholar 

  • Coyle D. E. (1998) Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23, 75–83.

    Article  PubMed  CAS  Google Scholar 

  • DeLeo J. A., Colburn R. W., Nichols M., and Malhotra A. (1996) Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J. Interferon Cytokine Res. 16, 695–700.

    Article  PubMed  CAS  Google Scholar 

  • Dmitrieva N., Rodriguez-Malaver A. J., Perez J., and Hernandez L. (2004) Differential release of neurotransmitters from superficial and deep layers of the dorsal horn in response to acute noxious stimulation and inflammation of the rat paw. Eur. J. Pain 8, 245–252.

    Article  PubMed  CAS  Google Scholar 

  • Dowdall T., Robinson I., and Meert T. F. (2005) Comparison of five different rat models of peripheral nerve injury. Pharmacol. Biochem. Behav. 80, 93–108.

    Article  PubMed  Google Scholar 

  • Durrenberger P. F., Facer P., Gray R. A., Chessell I. P., Naylor A., Bountra C., et al. (2004) Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury. J. Peripher. Nerv. Syst. 9, 15–25.

    Article  PubMed  CAS  Google Scholar 

  • Eckenstein F. P. (1994) Fibroblast growth factors in the nervous system. J. Neurobiol. 25, 1467–1480.

    Article  PubMed  CAS  Google Scholar 

  • Eclancher F., Kehrli P., Labourdette G., and Sensenbrenner M. (1996) Basic fibroblast growth factor (bFGF) injection activates the glial reaction in the injured adult rat brain. Brain Res. 737, 201–214.

    Article  PubMed  CAS  Google Scholar 

  • Eclancher F., Perraud F., Faltin J., Labourdette G., and Sensenbrenner M. (1990) Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain. Glia 3, 502–509.

    Article  PubMed  CAS  Google Scholar 

  • Eng L. F. (1985) Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astroyctes. J. Neuroimmunol. 8, 203–214.

    Article  PubMed  CAS  Google Scholar 

  • Fagan A. M., Suhr S. T., Lucidi-Phillipi C. A., Peterson D. A., Holtzman D. M., and Gage F. H. (1997) Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. J. Neurosci. 17, 2499–2511.

    PubMed  CAS  Google Scholar 

  • Figiel M., Maucher T., Rozyczka J., Bayatti N., and Engele J. (2003) Regulation of glial glutamate transporter expression by growth factors. Exp. Neurol. 183, 124–135.

    Article  PubMed  CAS  Google Scholar 

  • Garrison C. J., Dougherty P. M., Kajander K. C., and Carlton S. M. (1991) Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 565, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Goettl V. M., Hussain S.- R. A., Alzate O., Wirtz D. J., Stephens R. L. Jr., and Hackshaw K. V. (2004) Differential change in mRNA expression of p75 and Trk neurotrophin receptors in nucleus gracilis after spinal nerve ligation in the rat. Exp. Neurol. 187, 533–536.

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla F., Miller S., Choi J., and Cotman C. W. (1997) Heparan sulfate potentiates the autocrine action of basic fibroblast growth factor in astrocytes: an in vivo and in vitro study. Neuroscience 76, 137–145.

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla F., Vu L., and Cotman C. W. (1995) Regulation of astrocyte proliferation by FGF-2 and heparan sulfate in vivo. J. Neurosci. 15, 2021–2029.

    PubMed  CAS  Google Scholar 

  • Gonzalez A. M., Berry M., Maher P. A., Logan A., and Baird A. (1995) A comprehensive analysis of the distribution of FGF-2 and FGFR1 in the rat brain. Brain Res. 701, 201–226.

    Article  PubMed  CAS  Google Scholar 

  • Grothe C., Meisinger C., and Claus P. (2001) In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia. J. Comp. Neurol. 434, 342–257.

    Article  PubMed  CAS  Google Scholar 

  • Herzberg U. and Sagen J. (2001) Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J. Neuroimmunol. 116, 29–39.

    Article  PubMed  CAS  Google Scholar 

  • Himmelseher S., Pfenninger E., and Georgieff M. (1996) The effect of basic fibroblast growth factor on glutamate-injured neuroarchitecture and arachidonic acid release in adult hippocampal neurons. Brain Res. 707, 54–63.

    Article  PubMed  CAS  Google Scholar 

  • Holguin A., O’Connor K. A., Biedenkapp J., Campisi J., Wieseler-Frank J., Milligan E. D., et al. (2004) HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110, 517–530.

    Article  PubMed  CAS  Google Scholar 

  • Inklestein S. P., Kemmou A., Caday C. G., and Berlove D. J. (1993) Basic fibroblast growth factor protects cerebrocortical neurons against excitatory amino acid toxicity in vitro. Stroke 24, 141–143.

    Google Scholar 

  • Jaye M., Schlessinger J., and Dionne C. A. (1992) Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim. Biophys. Acta 1135, 185–199.

    Article  PubMed  CAS  Google Scholar 

  • Jensen T. S., Gottrup H., Sindrup S. H., and Bach F. W. (2001) The clinical picture of neuropathic pain. Eur. J. Pharmacol. 429, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Jin S.-X., Zhuang Z.-Y., Woolf C. J., and Ji R.-R. (2003) p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 23, 4017–4022.

    PubMed  CAS  Google Scholar 

  • Jorum E., Warncke T., and Stubhaug A. (2003) Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine—a double-blind, cross-over comparison with alfentanil and placebo. Pain 101, 229–235.

    Article  PubMed  CAS  Google Scholar 

  • Kamiguchi H., Yoshida K., Wakamoto H., Inaba M., Sasaki H., Otani M., and Toya S. (1996) Cytokine-induced selective increase of high-molecular-weight bFGF isoforms and their subcellular kinetics in cultured rat hippocampal astrocytes. Neurochem. Res. 21, 701–706.

    Article  PubMed  CAS  Google Scholar 

  • Kawamata M. and Omote K. (1996) Involvement of increased excitatory amino acids and intracellular Ca2+ concentration in the spinal dorsal horn in an animal model of neuropathic pain. Pain 68, 85–96.

    Article  PubMed  CAS  Google Scholar 

  • Kim S.-H. and Chung J.-M. (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–563.

    Article  PubMed  CAS  Google Scholar 

  • Lin C.-R., Wang C.-H., Wu P., Wen Z.-H., Buerkle H., and Yang L.-C. (2002) Apraclonidine attenuates the increases in spinal excitatory amino acid release in rats with adjuvant-induced inflammation. Anesth. Analg. 94, 701–705.

    Article  PubMed  CAS  Google Scholar 

  • Liu X., Mashour G. A., Webster H. F., and Kurtz A. (1998) Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. Glia 24, 390–397.

    Article  PubMed  CAS  Google Scholar 

  • Madiai F., Hussain S.- R. A., Goettl V. M., Burry R. W., Stephens R. L. Jr., and Hackshaw K. V. (2003) Upregulation of FGF-2 in reactive spinal cord astrocytes following unilateral lumbar spinal nerve ligation. Exp. Brain Res. 148, 366–376.

    PubMed  CAS  Google Scholar 

  • Meller S. T., Dykstra C., Grzybycki D., Murphy S., and Gebhart G. F. (1994) The possible role of glial in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33, 1471–1478.

    Article  PubMed  CAS  Google Scholar 

  • Merighi A., Carmignoto G., Gobbo S., Lossi L., Salio C., Vergnano A. M., and Zonta M. (2004) Neurotrophins in spinal cord nociceptive pathways. Prog. Brain Res. 146, 291–321.

    Article  PubMed  CAS  Google Scholar 

  • Messersmith D. J., Murtie J. C., Le T. Q., Frost E. E., and Armstrong R. C. (2000) Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. J. Neurosci. Res. 62, 241–256.

    Article  PubMed  CAS  Google Scholar 

  • Mestre C., Pelissier T., Fialip J., Wilcox G., and Eschalier A. (1994) A method to perform direct transcutaneous intrathecal injection in rats. J. Pharmacol. Toxicol. Methods 32, 197–200.

    Article  PubMed  CAS  Google Scholar 

  • Milligan E. D., O’Connor K. A., Nguyen K. T., Armstrong C. B., Twining C., Gaykema R. P., et al. (2001) Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord pro- inflammatory cytokines. J. Neurosci. 21, 2808–2819.

    PubMed  CAS  Google Scholar 

  • Moffett J., Kratz E., Myers J., Stachowiak E. K., Florkiewicz R. Z., and Stachowiak M. K. (1998) Transcriptional regulation of fibroblast growth factor-2 expression in human astrocytes: implications for cell plasticity. Mol. Biol. Cell 9, 2269–2285.

    PubMed  CAS  Google Scholar 

  • Nudel U., Zakut R., Shani M., Neuman S., Levy Z., and Yaffe D. (1983) The nucleotide sequence of the rat cytoplasmic beta-actin gene. Nucleic Acids Res. 11, 1759–1771.

    Article  PubMed  CAS  Google Scholar 

  • O’Banion M. K., Miller J. C., Chang J.-W., Kaplan M. D., and Coleman P. D. (1996) Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures. J. Neurochem. 66, 2532–2540.

    Article  PubMed  CAS  Google Scholar 

  • Ohtori S., Takahashi K., Moriya H., and Myers R. R. (2004) TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine 29, 1082–1088.

    Article  PubMed  Google Scholar 

  • Perraud F., Labourdette G., Eclancher F., and Sensenbrenner M. (1990) Primary cultures of astrocytes from different brain areas of newborn rats and effects of basic fibroblast growth factor. Dev. Neurosci. 12, 11–21.

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V., Tanga F. Y., and DeLeo J. A. (2004) Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 29, 327–334.

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V., Tanga F., and DeLeo J. A. (2003a) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624–630.

    Article  PubMed  CAS  Google Scholar 

  • Raghavendra V., Tanga F., Rutkowski M. D., and DeLeo J. A. (2003b) Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines. Pain 104, 655–664.

    Article  PubMed  CAS  Google Scholar 

  • Reeve A. J., Patel S., Fox A., Walker K., and Urban L. (2000) Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur. J. Pain 4, 247–257.

    Article  PubMed  CAS  Google Scholar 

  • Romero M. I., Rangappa N., Li L., Lightfoot E., Garry M. G., and Smith G. M. (2000) Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J. Neurosci. 20, 4435–4445.

    PubMed  CAS  Google Scholar 

  • Rowntree S. and Kolb B. (1997) Blockade of basic fibroblast growth factor retards recovery from motor cortex injury in rats. Eur. J. Neurosci. 9, 2432–2441.

    Article  PubMed  CAS  Google Scholar 

  • Rydh-Rinder M., Kerekes N., Svensson M., and Hokfelt T. (2001) Glutamate release from adult primary sensory neurons in culture is modulated by growth factors. Regul. Pept. 102, 69–79.

    Article  PubMed  CAS  Google Scholar 

  • Schlüter K., Figiel M., Rozyczka J., and Engele J. (2002) CNS region-specific regulation of glial glutamate transporter expression. Eur. J. Neurosci. 16, 836–842.

    Article  PubMed  Google Scholar 

  • Switzer S. M. and DeLeo J. A. (2002) The active metabolite of leflunomide, an immunosuppressive agent, reduces mechanical sensitivity in a rat mononeuropathy model. J. Pain 3, 360–368.

    Article  Google Scholar 

  • Sweitzer S., Martin D., and DeLeo J. A. (2001a) Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 103, 529–539.

    Article  PubMed  CAS  Google Scholar 

  • Sweitzer S. M., Schubert P., and DeLeo J. A. (2001b) Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J. Pharmacol. Exp. Ther. 297, 1210–1217.

    PubMed  CAS  Google Scholar 

  • Takeda K., Sawamura S., Sekiyama H., Tamai H., and Hanaoka K. (2004) Effect of methylprednisolone on neuropathic pain and spinal glial activation in rats. Anesthesiology 100, 1249–1257.

    Article  PubMed  CAS  Google Scholar 

  • Tanga F. Y., Raghavendra V., and DeLeo J. A. (2004) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem. Int. 45, 397–407.

    Article  PubMed  CAS  Google Scholar 

  • Vila M., Jackson-Lewis V., Guegan C., Wu D.-C., Teismann P., Choi D.- K., et al. (2001) The role of glial cellsin Parkinson’s disease. Curr. Opin. Neurol. 14, 483–489.

    Article  PubMed  CAS  Google Scholar 

  • Wang Z., Pekarskaya O., Bencheikh M., Chao W., Gelbard H. A., Ghorpade A., et al. (2003) Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120. Virology 312, 60–73.

    Article  PubMed  CAS  Google Scholar 

  • Wieseler-Frank J., Maier S. F., and Watkins L. R. (2004) Glial activation and pathological pain. Neurochem. Int. 45, 389–395.

    Article  PubMed  CAS  Google Scholar 

  • Winkelstein B. A., Rutkowski M. D., Sweitzer S. M., Pahl J. L., and DeLeo J. A. (2001) Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J. Comp. Neurol. 439, 127–139.

    Article  PubMed  CAS  Google Scholar 

  • Yoshida K. and Gage F. H. (1991) Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res. 538, 118–126.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, The Ohio State University, COlumbus, OH

    Francesca Madiai, Virginia M. Goettl, Syed-Rehan Hussain, Alec R. Clairmont & Kevin V. Hackshaw

  2. Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Virginia M. Goettl & Robert L. Stephens

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  1. Francesca Madiai
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  2. Virginia M. Goettl
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  3. Syed-Rehan Hussain
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Correspondence to Kevin V. Hackshaw.

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Madiai, F., Goettl, V.M., Hussain, SR. et al. Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain. J Mol Neurosci 27, 315–324 (2005). https://doi.org/10.1385/JMN:27:3:315

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  • DOI: https://doi.org/10.1385/JMN:27:3:315

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