Skip to main content

Advertisement

SpringerLink
Log in

Slow modulation of synaptic transmission by brain-derived neurotrophic factor leads to the central sensitization associated with neuropathic pain

  • Published:
Neurophysiology Aims and scope

Abstract

Chronic constriction injury (CCI) of the rat sciatic nerve increases the dorsal horn excitability. This “central sensitization” leads to behavioral manifestations analogous to those related to human neuropathic pain. We found, using whole-cell recording from acutely isolated spinal cord slices, that 7-to 10-day-long CCI increases excitatory synaptic drive to putative excitatory “delay”-firing neurons in the substantia gelatinosa but attenuates that to putative inhibitory “tonic”-firing neurons. A defined-medium organotypic culture (DMOTC) system was used to investigate the long-term actions of brain-derived neurotrophic factor (BDNF) as a possible instigator of these changes. When all five neuronal types found in the substantia gelatinosa were considered, BDNF and CCI produced similar patterns, or “footprints,” of changes across the whole population. This pattern was not seen with another putative “pain mediator,” interleukin 1β. Thus, BDNF decreased synaptic drive to “tonic” neurons and increased synaptic drive to “delay” neurons. Actions of BDNF on “delay” neurons were presynaptic and involved increased mEPSC frequency and amplitude without changes in the function of postsynaptic AMPA receptors. By contrast, BDNF exerted both pre-and post-synaptic actions on “ tonic” cells to reduce the mEPSC frequency and amplitude. These differential actions of BDNF on excitatory and inhibitory neurons contributed to a global increase in the dorsal horn network excitability as assessed by the amplitude of depolarization-induced increases in the intracellular [Ca2+]. Experiments with the BDNF-binding protein TrkB-d5 provided additional evidence for BDNF as a harbinger of neuropathic pain. Thus, the cellular processes altered by BDNF likely contribute to “central sensitization” and hence to the onset of neuropathic 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

Similar content being viewed by others

References

  1. L. G. Brock, J. S. Coombs, and J. C. Eccles, “The nature of the monosynaptic excitatory and inhibitory processes in the spinal cord,” Proc. Roy. Soc. London, Ser. B, Biol. Sci., 140, 170–176 (10-16-1952).

    CAS  Google Scholar 

  2. A. A. Selyanko, V. A. Derkach, and V. I. Skok, “Fast excitatory postsynaptic currents in voltage-clamped mammalian sympathetic ganglion neurons,” J. Auton. Nerv. Syst., 1, 127–137 (1979).

    Article  PubMed  CAS  Google Scholar 

  3. E. Florey, “Neurotransmitters and modulators in the animal kingdom,” Fed. Proc., 26, 1164–1178 (1967).

    PubMed  CAS  Google Scholar 

  4. J. C. Eccles, “Slow potential waves in the superior cervical ganglion,” J. Physiol., 85, 464–501 (1935).

    PubMed  CAS  Google Scholar 

  5. K. Kuba and K. Koketsu, “Synaptic events in sympathetic ganglia,” Prog. Neurobiol., 11, 77–169 (1978).

    Article  PubMed  CAS  Google Scholar 

  6. P. R. Adams and D. A. Brown, “Synaptic inhibition of the M-current: slow excitatory post-synaptic potential mechanism in bullfrog sympathetic neurons,” J. Physiol., 332, 263–272 (1982).

    PubMed  CAS  Google Scholar 

  7. H. Thoenen, “Neurotrophins and neuronal plasticity,” Science, 270, 593–598 (10-27-1995).

    Article  PubMed  CAS  Google Scholar 

  8. A. K. McAllister, L. C. Katz, and D. C. Lo, “Neurotrophins and synaptic plasticity,” Annu. Rev. Neurosci., 22, 295–318 (1999).

    Article  PubMed  CAS  Google Scholar 

  9. R. Stoop and M. M. Poo, “Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling,” Science, 267, 695–699 (2-3-1995).

    Article  PubMed  CAS  Google Scholar 

  10. R. Stoop and M. M. Poo, “Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor,” J. Neurosci., 16, 3256–3264 (5-15-1996).

    PubMed  CAS  Google Scholar 

  11. S. J. Kim and J. M. Chung, “An experimental model for peripheral neuropathy produced by segmental nerve ligation in the rat,” Pain, 50, 355–363 (1992).

    Article  PubMed  CAS  Google Scholar 

  12. K. J. Kim, Y. W. Yoon and J. M. Chung, “Comparison of three rodent models of neuropathic pain,” Exp. Brain Res., 113, 200–206 (1997).

    Article  PubMed  CAS  Google Scholar 

  13. S. R. Chen and H. L. Pan, “Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats,” J. Neurophysiol., 87, 2726–2733 (2002).

    PubMed  Google Scholar 

  14. P. A. Smith, “Neuropathic pain: drug targets for current and future interventions,” Drug News Perspect., 17, 5–17 (2004).

    Article  PubMed  CAS  Google Scholar 

  15. T. Mosconi and L. Kruger, “Fixed-diameter polyethylene cuffs applied to the rat sciatic nerve induce a painful neuropathy: ultrastructural morphometric analysis of axonal alterations,” Pain, 64, 37–57 (1996).

    Article  PubMed  CAS  Google Scholar 

  16. G. J. Bennett and Y.-K. Xie, “A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man,” Pain, 33, 87–107 (1988).

    Article  PubMed  CAS  Google Scholar 

  17. A. Dalal, M. Tata, G. Allegre, et al., “Spontaneous activity of rat dorsal horn cells in spinal segments of sciatic projection following transection of sciatic nerve or of corresponding dorsal roots,” Neuroscience, 94, 217–228 (1999).

    Article  PubMed  CAS  Google Scholar 

  18. T. Kohno, K. A. Moore, H. Baba, and C. J. Woolf, “Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn,” J. Physiol., 548, 131–138 (4-1-2003).

    Article  PubMed  CAS  Google Scholar 

  19. J. M. Laird and G. J. Bennett, “An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy,” J. Neurophysiol., 69, 2072–2085 (1993).

    PubMed  CAS  Google Scholar 

  20. C. J. Woolf, “Evidence for a central component of post-injury pain hypersensitivity,” Nature, 306, 686–688 (12-15-1983).

    Article  PubMed  CAS  Google Scholar 

  21. H. Baba, T. P. Doubell, and C. J. Woolf, “Peripheral inflammation facilitates Aα fiber-mediated synaptic input to the substantia gelatinosa of the adult rat spinal cord,” J. Neurosci., 19, 859–867 (1999).

    PubMed  CAS  Google Scholar 

  22. M. Tsuda, Y. Shigemoto-Mogami, S. Koizumi, et al., “P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury,” Nature, 424, 778–783 (8-14-2003).

    Article  PubMed  CAS  Google Scholar 

  23. M. Tsuda, K. Inoue, and M. W. Salter, “Neuropathic pain and spinal microglia: a big problem from molecules in ’small’ glia,” Trends Neurosci., 28, 101–107 (2005).

    Article  PubMed  CAS  Google Scholar 

  24. J. A. Coull, S. Beggs, D. Boudreau, et al., “BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain,” Nature, 438, 1017–1021 (12-15-2005).

    Article  PubMed  CAS  Google Scholar 

  25. G. M. Verge, E. D. Milligan, S. F. Maier, et al., “Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions,” Eur. J. Neurosci., 20, 1150–1160 (2004).

    Article  PubMed  Google Scholar 

  26. J. Zhang and Y. De Koninck, “Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury,” J. Neurochem., 97, 772–783 (2006).

    Article  PubMed  CAS  Google Scholar 

  27. S. Balasubramanyan, P. L. Stemkowski, M. J. Stebbing, and P. A. Smith, “Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat substantia gelatinosa neurons,” J. Neurophysiol., 96, 579–590 (2006).

    Article  PubMed  Google Scholar 

  28. S. Gobel, “Golgi studies of the neurons in layer II of the dorsal horn of the medulla (trigeminal nucleus caudalis,” J. Comp. Neurol., 180, 395–414 (1978).

    Article  PubMed  CAS  Google Scholar 

  29. A. J. Todd and S. G. Lewis, “The morphology of Golgi-stained neurons in lamina II of the rat spinal cord,” J. Anat., 149, 113–119 (1986).

    PubMed  CAS  Google Scholar 

  30. A. J. Todd and R. C. Spike, “The localization of classical transmitters and neuropeptides within neurons in laminae IIII of the mammalian spinal dorsal horn,” Prog. Neurobiol., 41, 609–645 (1993).

    Article  PubMed  CAS  Google Scholar 

  31. Y. Lu and E. R. Perl, “Modular organization of excitatory circuits between neurons of the spinal superficial dorsal horn (laminae I and II),” J. Neurosci., 25, 3900–3907 (4-13-2005).

    Article  PubMed  CAS  Google Scholar 

  32. S. C. Apfel, D. E. Wright, A. M. Wiideman, et al., “Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system,” Mol. Cell Neurosci., 7, 134–142 (1996).

    Article  PubMed  CAS  Google Scholar 

  33. S. Matayoshi, N. Jiang, T. Katafuchi, et al., “Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat,” J. Physiol., 569, 685–695 (12-1-2005).

    Article  PubMed  CAS  Google Scholar 

  34. H. J. Cho, J. K. Kim, H. C. Park, et al., “Changes in brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia, spinal cord, and gracile nuclei following cut or crush injuries,” Exp. Neurol., 154, 224–230 (1998).

    Article  PubMed  CAS  Google Scholar 

  35. K. D. Dougherty, C. F. Dreyfus and I. B. Black, “Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury,” Neurobiol. Dis., 7, 574–585 (2000).

    Article  PubMed  CAS  Google Scholar 

  36. T. Fukuoka, E. Kondo, Y. Dai, et al., “Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model,” J. Neurosci., 21, 4891–4900 (7-1-2001).

    PubMed  CAS  Google Scholar 

  37. S. O. Ha, J. K. Kim, H. S. Hong, et al., “Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain,” Neuroscience, 107, 301–309 (2001).

    Article  PubMed  CAS  Google Scholar 

  38. G. J. Michael, S. Averill, P. J. Shortland, et al., “Axotomy results in major changes in BDNF expression by dorsal root ganglion cells: BDNF expression in large trkB and trkC cells, in pericellular baskets, and in projections to deep dorsal horn and dorsal column nuclei,” Eur. J. Neurosci., 11, 3539–3551 (1999).

    Article  PubMed  CAS  Google Scholar 

  39. G. Miletic and V. Miletic, “Increases in the concentration of brain-derived neurotrophic factor in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats,” Neurosci. Lett., 319, 137–140 (2-22-2002).

    Article  PubMed  CAS  Google Scholar 

  40. H. J. Cho, J. K. Kim, X. F. Zhou, and R. A. Rush, “Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation,” Brain Res., 764, 269–272 (8-1-1997).

    Article  PubMed  CAS  Google Scholar 

  41. T. Fukuoka, E. Kondo, Y. Dai, et al., “Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model,” J. Neurosci., 21, 4891–4900 (7-1-2001).

    PubMed  CAS  Google Scholar 

  42. X. F. Zhou, E. T. Chie, Y. S. Deng, et al., “Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat,” Neuroscience, 92, 841–853 (1999).

    Article  PubMed  CAS  Google Scholar 

  43. S. M. Garraway, J. C. Petruska, and L. M. Mendell, “BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs,” Eur. J. Neurosci., 18, 2467–2476 (2003).

    Article  PubMed  Google Scholar 

  44. S. M. Garraway, A. J. Anderson, and L. M. Mendell, “BDNF-induced facilitation of afferent-evoked responses in lamina II neurons is reduced after neonatal spinal cord contusion injury,” J. Neurophysiol., 94, 1798–1804 (2005).

    Article  PubMed  CAS  Google Scholar 

  45. B. J. Kerr, E. J. Bradbury, D. L. Bennett, et al., “Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord,” J. Neurosci., 19, 5138–5148 (6-15-1999).

    PubMed  CAS  Google Scholar 

  46. S. E. Slack and S. W. Thompson, “Brain-derived neurotrophic factor induces NMDA receptor 1 phosphorylation in rat spinal cord,” NeuroReport, 13, 1967–1970 (10-28-2002).

    Article  PubMed  CAS  Google Scholar 

  47. V. B. Lu, T.D. Moran, S. Balasubramanyan, et al., “Substantia gelatinosa neurons in defined-medium organotypic slice culture are similar to those in acute slices from young adult rats,” Pain, 121, 261–275 (2006).

    Article  PubMed  Google Scholar 

  48. A. Ruangkittisakul, S. W. Schwarzacher, L. Secchia, et al., “High sensitivity to neuromodulator-activated signaling pathways at physiological [K+] of confocally imaged respiratory center neurons in on-line-calibrated newborn rat brainstem slices,” J. Neurosci., 26, 11870–11880 (2006).

    Article  PubMed  CAS  Google Scholar 

  49. S. L. Stuesse, W. L. Cruce, J. A. Lovell, et al., “Microglial proliferation in the spinal cord of aged rats with a sciatic nerve injury,” Neurosci. Lett., 287, 121–124 (6-23-2000).

    Article  PubMed  CAS  Google Scholar 

  50. A. K. Clark, C. Gentry, E. J. Bradbury, et al., “Role of spinal microglia in rat models of peripheral nerve injury and inflammation,” Eur. J. Pain, (3-16-2006).

  51. E. Milligan, V. Zapata, D. Schoeniger, et al., “An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine,” Eur. J. Neurosci., 22, 2775–2782 (2005).

    Article  PubMed  CAS  Google Scholar 

  52. B. C. Hains and S. G. Waxman, “Activated microglia contribute to the maintenance of chronic pain after spinal cord injury,” J. Neurosci., 26, 4308–4317 (4-19-2006).

    Article  PubMed  CAS  Google Scholar 

  53. A. K. Clark, F. D’Aquisto, C. Gentry, et al., “Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation,” J. Neurochem., 99, 868–880 (2006).

    Article  PubMed  CAS  Google Scholar 

  54. A. Y. Lai and K. G. Todd, “Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines,” Glia, 53, 809–816 (2006).

    Article  PubMed  Google Scholar 

  55. M. J. Banfield, R. L. Naylor, A. G. Robertson, et al., “Specificity in Trk receptor-neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5,” Structure, 9, 1191–1199 (2001).

    Article  PubMed  CAS  Google Scholar 

  56. S. W. Thompson, D. L. Bennett, B. J. Kerr, et al., “Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord,” Proc. Natl. Acad. Sci. USA, 96, 7714–7718 (7-6-1999).

    Article  PubMed  CAS  Google Scholar 

  57. M. Meyer, I. Matsuoka, C. Wetmore, et al., “Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA,” J. Cell. Biol., 119, 45–54 (1992).

    Article  PubMed  CAS  Google Scholar 

  58. I. J. Lever, E. J. Bradbury, J. R. Cunningham, et al., “Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation,” J. Neurosci., 21, 4469–4477 (6-15-2001).

    PubMed  CAS  Google Scholar 

  59. K. Kohara, A. Kitamura, M. Morishima, and T. Tsumoto, “Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons,” Science, 291, 2419–2423 (3-23-2001).

    Article  PubMed  CAS  Google Scholar 

  60. Y. Yajima, M. Narita, N. Matsumoto, et al., “Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB pathway in the development of nerve injury-induced thermal hyperalgesia in mice,” Brain Res., 958, 338–346 (12-27-2002).

    Article  PubMed  CAS  Google Scholar 

  61. L. R. Watkins, S. F. Maier, and L. E. Goehler, “Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states,” Pain, 63, 289–302 (1995).

    Article  PubMed  CAS  Google Scholar 

  62. A. Ledeboer, E. M. Sloane, E. D. Milligan, et al., “Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation,” Pain, 115, 71–83 (2005).

    Article  PubMed  CAS  Google Scholar 

  63. A. Ledeboer, J. H. Mahoney, E. D. Milligan, et al., “Spinal cord glia and interleukin-1 do not appear to mediate persistent allodynia induced by intramuscular acidic saline in rats,” J. Pain, 7, 757–767 (2006).

    Article  PubMed  CAS  Google Scholar 

  64. V. B. Lu, M. J. S. Chee, S. L. Gustafson, et al., “Concentration-dependent effects of long-term interleukin-1 treatment on spinal dorsal horn neurons in organotypic slice cultures,” Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, Online, 292.3-(2005).

  65. S. Echeverry, X. Q. Shi, and J. Zhang, “Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain,” Pain, (6-7-2007).

  66. A. K. Clark, P. K. Yip, J. Grist, et al., “Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain,” Proc. Natl. Acad. Sci. USA, 104, 10655–10660 (6-19-2007).

    Article  PubMed  CAS  Google Scholar 

  67. A. Moss, S. Beggs, D. Vega-Avelaira, et al., “Spinal microglia and neuropathic pain in young rats,” Pain, 128, 215–224 (2007).

    Article  PubMed  CAS  Google Scholar 

  68. R. Groth and L. Aanonsen, “Spinal brain-derived neurotrophic factor (BDNF) produces hyperalgesia in normal mice while antisense directed against either BDNF or trkB, prevent inflammation-induced hyperalgesia,” Pain, 100, 171–181 (2002).

    Article  PubMed  CAS  Google Scholar 

  69. R. J. Mannion, M. Costigan, I. Decosterd, et al., “Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity,” Proc. Natl. Acad. Sci. USA, 96, 9385–9390 (8-3-1999).

    Article  PubMed  CAS  Google Scholar 

  70. T. J. Grudt and E. R. Perl, “Correlations between neuronal morphology and electrophysiological features in the rodent superficial dorsal horn,” J. Physiol., 540, 189–207 (4-1-2002).

    Article  PubMed  CAS  Google Scholar 

  71. Y. Lu and E. R. Perl, “A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input,” J. Neurosci., 23, 8752–8758 (9-24-2003).

    PubMed  CAS  Google Scholar 

  72. H. Baba, R. R. Ji, T. Kohno, et al., “Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn,” Mol. Cell Neurosci., 24, 818–830 (2003).

    Article  PubMed  CAS  Google Scholar 

  73. K. A. Moore, T. Kohno, L. A. Karchewski, et al., “Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord,” J. Neurosci., 22, 6724–6731 (8-1-2002).

    PubMed  CAS  Google Scholar 

  74. L. Sivilotti and C. J. Woolf, “The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord,” J. Neurophysiol., 72, 169–179 (1994).

    PubMed  CAS  Google Scholar 

  75. F. J. Alvarez, R. M. Villalba, R. Zerda, and S. P. Schneider, “Vesicular glutamate transporters in the spinal cord, with special reference to sensory primary afferent synapses,” J. Comp. Neurol., 472, 257–280 (5-3-2004).

    Article  PubMed  CAS  Google Scholar 

  76. A. L. Oliveira, F. Hydling, E. Olsson, et al., “Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia,” Synapse, 50, 117–129 (2003).

    Article  PubMed  CAS  Google Scholar 

  77. A. L. Bailey and A. Ribeiro-da-Silva, “Transient loss of terminals from non-peptidergic nociceptive fibers in the substantia gelatinosa of spinal cord following chronic constriction injury of the sciatic nerve,” Neuroscience, 138, 675–690 (2006).

    Article  PubMed  CAS  Google Scholar 

  78. K. Dougherty, M. A. Sawchuk, and S. Hochman, “Properties of mouse spinal lamina I GABAergic interneurons,” J. Neurophysiol., 94, 3221–3227 (7-13-2005).

    Article  PubMed  Google Scholar 

  79. A. W. Hantman, A. N. van den Pol, and E. R. Perl, “Morphological and physiological features of a set of spinal substantia gelatinosa neurons defined by green fluorescent protein expression,” J. Neurosci., 24, 836–842 (1-28-2004).

    Article  PubMed  CAS  Google Scholar 

  80. A. Galan, J. M. A. Laird, and F. Cervero, “In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons,” Pain, 112, 315–323 (2004).

    Article  PubMed  CAS  Google Scholar 

  81. G. G. Nagy, M. Al Ayyan, D. Andrew, et al., “Widespread expression of the AMPA receptor GluR2 subunit at glutamatergic synapses in the rat spinal cord and phosphorylation of GluR1_in response to noxious stimulation revealed with an antigen-unmasking method,” J. Neurosci., 24, 5766–5777 (6-23-2004).

    Article  PubMed  CAS  Google Scholar 

  82. K. Wu, G. W. Len, G. McAuliffe, et al., “Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms,” Brain Res. Mol. Brain Res., 130, 178–186 (11-4-2004).

    Article  PubMed  CAS  Google Scholar 

  83. P. Menei, C. Montero-Menei, S. R. Whittemore, et al., “Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord,” Eur. J. Neurosci., 10, 607–621 (1998).

    Article  PubMed  CAS  Google Scholar 

  84. J. G. Boyd and T. Gordon, “The neurotrophin receptors, trkB and p75, differentially regulate motor axonal regeneration,” J. Neurobiol., 49, 314–325 (2001).

    Article  PubMed  CAS  Google Scholar 

  85. Y. Liu, B. T. Himes, M. Murray, et al., “Grafts of BDNF-producing fibroblasts rescue axotomized rubrospinal neurons and prevent their atrophy,” Exp. Neurol., 178, 150–164 (2002).

    Article  PubMed  CAS  Google Scholar 

  86. C. A. Tobias, J. S. Shumsky, M. Shibata, et al., “Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration,” Exp. Neurol., 184, 97–113 (2003).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Alberta, Edmonton, Canada

    Van B. Lu, S. Balasubramanyan, J. E. Biggs, S. L. Gustafson, K. Todd, A. Lai, W. F. Colmers, K. Ballanyi & P. A. Smith

  2. RMIT University, Bundoora, Australia

    M. J. Stebbing

  3. University of Bristol, Bristol, Great Britain

    D. Dawbarn

Authors
  1. Van B. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Balasubramanyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. E. Biggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. J. Stebbing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. L. Gustafson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Todd
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Dawbarn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W. F. Colmers
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K. Ballanyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P. A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. A. Smith.

Additional information

Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 315–326, July–October, 2007.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, V.B., Balasubramanyan, S., Biggs, J.E. et al. Slow modulation of synaptic transmission by brain-derived neurotrophic factor leads to the central sensitization associated with neuropathic pain. Neurophysiology 39, 272–283 (2007). https://doi.org/10.1007/s11062-007-0038-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11062-007-0038-1

Keywords

Search

Navigation