Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2011 | Research

Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitrostudy

Authors: Ya-Tin Lin, Long-Sun Ro, Hung-Li Wang, Jin-Chung Chen

Published in: Journal of Neuroinflammation | Issue 1/2011

Abstract

Background

During inflammation, immune cells accumulate in damaged areas and release pro-inflammatory cytokines and neurotrophins. Brain-derived neurotrophic factor (BDNF) plays a neuromodulatory role in spinal cord dorsal horn via the post-synaptic tyrosine protein kinase B (trkB) receptor to facilitate pain transmission. However, the precise role of BDNF and trkB receptor in the primary sensory neurons of dorsal root ganglia (DRG) during inflammation remains to be clarified. The aim of this study was to investigate whether and how BDNF-trkB signaling in the DRG is involved in the process of inflammatory pain.

Methods

We used complete Freund's adjuvant- (CFA-) induced and tumor necrosis factor-α- (TNF-α-) induced inflammation in rat hindpaw as animal models of inflammatory pain. Quantification of protein and/or mRNA levels of pain mediators was performed in separate lumbar L3-L5 DRGs. The cellular mechanism of TNF-α-induced BDNF and/or trkB receptor expression was examined in primary DRG cultures collected from pooled L1-L6 DRGs. Calcitonin gene-related peptide (CGRP), BDNF and substance P release were also evaluated by enzyme immunoassay.

Results

CFA injection into rat hindpaw resulted in mechanical hyperalgesia and significant increases in levels of TNF-α in the inflamed tissues, along with enhancement of BDNF and trkB receptor as well as the pain mediators CGRP and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in DRG. Direct injection of TNF-α into rat hindpaw resulted in similar effects with retrograde transport of TNF-α along the saphenous nerve to DRG during CFA-induced inflammation. Primary DRG cultures chronically treated with TNF-α showed significant enhancement of mRNA and protein levels of BDNF and trkB receptor, BDNF release and trkB-induced phospho-ERK1/2 signal. Moreover, CGRP and substance P release were enhanced in DRG cultures after chronic TNF-α treatment or acute BDNF stimulation. In addition, we found that BDNF up-regulated trkB expression in DRG cultures.

Conclusions

Based on our current experimental results, we conclude that inflammation and TNF-α up-regulate the BDNF-trkB system in DRG. This phenomenon suggests that up-regulation of BDNF in DRG may, in addition to its post-synaptic effect in spinal dorsal horn, act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission, thereby contributing to the development of hyperalgesia.

Available only for authorised users

Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV: Anti-TNF-neutralizing antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy. Brain Res. 2001, 913: 86-89. 10.1016/S0006-8993(01)02743-3.CrossRefPubMed

Zhang JH, Huang YG: The immune system: a new look at pain. Chin Med J (Engl). 2006, 119: 930-938.

Coutaux A, Adam F, Willer JC, Le Bars D: Hyperalgesia and allodynia: peripheral mechanisms. Joint Bone Spine. 2005, 72: 359-371. 10.1016/j.jbspin.2004.01.010.CrossRefPubMed

Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature. 2001, 413: 203-210. 10.1038/35093019.CrossRefPubMed

Planells-Cases R, Garcia-Sanz N, Morenilla-Palao C, Ferrer-Montiel A: Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflugers Arch. 2005, 451: 151-159. 10.1007/s00424-005-1423-5.CrossRefPubMed

Sommer C, Kress M: Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004, 361: 184-187. 10.1016/j.neulet.2003.12.007.CrossRefPubMed

Fehrenbacher JC, Burkey TH, Nicol GD, Vasko MR: Tumor necrosis factor alpha and interleukin-1beta stimulate the expression of cyclooxygenase II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root ganglia cells. Pain. 2005, 113: 113-122. 10.1016/j.pain.2004.09.031.CrossRefPubMed

Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH: The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol. 1992, 107: 660-664.PubMedCentralCrossRefPubMed

Sommer C, Schmidt C, George A: Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp Neurol. 1998, 151: 138-142. 10.1006/exnr.1998.6797.CrossRefPubMed

10.

Cunha TM, Verri WA, Silva JS, Poole S, Cunha FQ, Ferreira SH: A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA. 2005, 102: 1755-1760. 10.1073/pnas.0409225102.PubMedCentralCrossRefPubMed

11.

Hensellek S, Brell P, Schaible HG, Brauer R, Segond von Banchet G: The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci. 2007, 36: 381-391. 10.1016/j.mcn.2007.07.010.CrossRefPubMed

12.

Ernsberger U: Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. Cell Tissue Res. 2009, 336: 349-384. 10.1007/s00441-009-0784-z.CrossRefPubMed

13.

Mendell LM, Albers KM, Davis BM: Neurotrophins, nociceptors, and pain. Microscopy research and technique. 1999, 45: 252-261. 10.1002/(SICI)1097-0029(19990515/01)45:4/5<252::AID-JEMT9>3.0.CO;2-N.CrossRefPubMed

14.

Zhu W, Oxford GS: Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1. Mol Cell Neurosci. 2007, 34: 689-700. 10.1016/j.mcn.2007.01.005.PubMedCentralCrossRefPubMed

15.

Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron. 2002, 36: 57-68. 10.1016/S0896-6273(02)00908-X.CrossRefPubMed

16.

Apfel SC, Wright DE, Wiideman AM, Dormia C, Snider WD, Kessler JA: Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system. Mol Cell Neurosci. 1996, 7: 134-142. 10.1006/mcne.1996.0010.CrossRefPubMed

17.

Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q, Priestley JV: Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci. 1997, 17: 8476-8490.PubMed

18.

Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R: BDNF as a pain modulator. Prog Neurobiol. 2008, 85: 297-317. 10.1016/j.pneurobio.2008.04.004.CrossRefPubMed

19.

Obata K, Noguchi K: BDNF in sensory neurons and chronic pain. Neurosci Res. 2006, 55: 1-10. 10.1016/j.neures.2006.01.005.CrossRefPubMed

20.

Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB, et al: Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci. 2006, 31: 539-548. 10.1016/j.mcn.2005.11.008.CrossRefPubMed

21.

Salio C, Lossi L, Ferrini F, Merighi A: Ultrastructural evidence for a pre- and postsynaptic localization of full-length trkB receptors in substantia gelatinosa (lamina II) of rat and mouse spinal cord. Eur J Neurosci. 2005, 22: 1951-1966. 10.1111/j.1460-9568.2005.04392.x.CrossRefPubMed

22.

Matayoshi S, Jiang N, Katafuchi T, Koga K, Furue H, Yasaka T, Nakatsuka T, Zhou XF, Kawasaki Y, Tanaka N, Yoshimura M: Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat. J Physiol. 2005, 569: 685-695. 10.1113/jphysiol.2005.095331.PubMedCentralCrossRefPubMed

23.

Merighi A, Bardoni R, Salio C, Lossi L, Ferrini F, Prandini M, Zonta M, Gustincich S, Carmignoto G: Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord. Dev Neurobiol. 2008, 68: 457-475. 10.1002/dneu.20605.CrossRefPubMed

24.

Groth R, Aanonsen L: Spinal brain-derived neurotrophic factor (BDNF) produces hyperalgesia in normal mice while antisense directed against either BDNF or trkB, prevent inflammation-induced hyperalgesia. Pain. 2002, 100: 171-181. 10.1016/S0304-3959(02)00264-6.CrossRefPubMed

25.

Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, Williams RJ, McMahon SB: Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol Cell Neurosci. 2002, 21: 684-695. 10.1006/mcne.2002.1205.CrossRefPubMed

26.

Fruhstorfer H, Gross W, Selbmann O: von Frey hairs: new materials for a new design. Eur J Pain. 2001, 5: 341-342. 10.1053/eujp.2001.0250.CrossRefPubMed

27.

Deruddre S, Combettes E, Estebe JP, Duranteau J, Benhamou D, Beloeil H, Mazoit JX: Effects of a bupivacaine nerve block on the axonal transport of Tumor Necrosis Factor-alpha (TNF-α) in a rat model of carrageenan-induced inflammation. Brain Behav Immun. 2010, 24: 652-659. 10.1016/j.bbi.2010.01.013.CrossRefPubMed

28.

Shubayev VI, Myers RR: Axonal transport of TNF-α in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol. 2001, 114: 48-56. 10.1016/S0165-5728(00)00453-7.CrossRefPubMed

29.

Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ: Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci USA. 1999, 96: 9385-9390. 10.1073/pnas.96.16.9385.PubMedCentralCrossRefPubMed

30.

Chien CC, Fu WM, Huang HI, Lai YH, Tsai YF, Guo SL, Wu TJ, Ling QD: Expression of neurotrophic factors in neonatal rats after peripheral inflammation. J Pain. 2007, 8: 161-167. 10.1016/j.jpain.2006.07.004.CrossRefPubMed

31.

Qiao LY, Grider JR: Up-regulation of calcitonin gene-related peptide and receptor tyrosine kinase TrkB in rat bladder afferent neurons following TNBS colitis. Experimental Neurology. 2007, 204: 667-679. 10.1016/j.expneurol.2006.12.024.PubMedCentralCrossRefPubMed

32.

Qiao LY, Vizzard AM: Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression and phosphorylation in rat micturition pathways. J Comp Neurol. 2002, 454: 200-211. 10.1002/cne.10447.CrossRefPubMed

33.

Qiao LY, Vizzard MA: Spinal cord injury-induced expression of TrkA, TrkB, phosphorylated CREB, and c-Jun in rat lumbosacral dorsal root ganglia. J Comp Neurol. 2005, 482: 142-154. 10.1002/cne.20394.CrossRefPubMed

34.

Cho HJ, Kim SY, Park MJ, Kim DS, Kim JK, Chu MY: Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation. Brain Res. 1997, 749: 358-362. 10.1016/S0006-8993(97)00048-6.CrossRefPubMed

35.

Cho HJ, Kim JK, Zhou XF, Rush RA: Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res. 1997, 764: 269-272. 10.1016/S0006-8993(97)00597-0.CrossRefPubMed

36.

Balkowiec-Iskra E, Vermehren-Schmaedick A, Balkowiec A: Tumor necrosis factor-alpha increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner. Neuroscience. 2011, 180: 322-333.PubMedCentralCrossRefPubMed

37.

Bajrovic F, Sketelj J: Extent of nociceptive dermatomes in adult rats is not primarily maintained by axonal competition. Exp Neurol. 1998, 150: 115-121. 10.1006/exnr.1997.6734.CrossRefPubMed

38.

Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, Fukuoka T, Tokunaga A, Noguchi K: Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci. 2004, 24: 10211-10222. 10.1523/JNEUROSCI.3388-04.2004.CrossRefPubMed

39.

Schafers M, Sorkin LS, Geis C, Shubayev VI: Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci Lett. 2003, 347: 179-182. 10.1016/S0304-3940(03)00695-5.CrossRefPubMed

40.

Schafers M, Lee DH, Brors D, Yaksh TL, Sorkin LS: Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci. 2003, 23: 3028-3038.PubMed

41.

Grimsholm O, Rantapaa-Dahlqvist S, Dalen T, Forsgren S: BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters. Clin Rheumatol. 2008, 27: 1289-1297. 10.1007/s10067-008-0910-4.CrossRefPubMed

42.

Woolf CJ, Allchorne A, Safieh-Garabedian B, Poole S: Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol. 1997, 121: 417-424. 10.1038/sj.bjp.0701148.PubMedCentralCrossRefPubMed

43.

Pezet S, Malcangio M, McMahon SB: BDNF: a neuromodulator in nociceptive pathways?. Brain Res Brain Res Rev. 2002, 40: 240-249.CrossRefPubMed

44.

Grund EM, Kagan D, Tran CA, Zeitvogel A, Starzinski-Powitz A, Nataraja S, Palmer SS: Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells. Mol Pharmacol. 2008, 73: 1394-1404. 10.1124/mol.107.042176.CrossRefPubMed

45.

Utreras E, Futatsugi A, Rudrabhatla P, Keller J, Iadarola MJ, Pant HC, Kulkarni AB: Tumor necrosis factor-alpha regulates cyclin-dependent kinase 5 activity during pain signaling through transcriptional activation of p35. J Biol Chem. 2009, 284: 2275-2284.PubMedCentralCrossRefPubMed

46.

Bonnington JK, McNaughton PA: Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol. 2003, 551: 433-446. 10.1113/jphysiol.2003.039990.PubMedCentralCrossRefPubMed

47.

Saha RN, Liu X, Pahan K: Up-regulation of BDNF in astrocytes by TNF-α: a case for the neuroprotective role of cytokine. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2006, 1: 212-222.CrossRef

48.

Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM: A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995, 374: 450-453. 10.1038/374450a0.CrossRefPubMed

49.

Ferrer I, Ballabriga J, Marti E, Perez E, Alberch J, Arenas E: BDNF up-regulates TrkB protein and prevents the death of CA1 neurons following transient forebrain ischemia. Brain Pathol. 1998, 8: 253-261.CrossRefPubMed

50.

Bowen EJ, Schmidt TW, Firm CS, Russo AF, Durham PL: Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons. J Neurochem. 2006, 96: 65-77. 10.1111/j.1471-4159.2005.03524.x.PubMedCentralCrossRefPubMed

51.

Ansel JC, Brown JR, Payan DG, Brown MA: Substance P selectively activates TNF-α gene expression in murine mast cells. J Immunol. 1993, 150: 4478-4485.PubMed

52.

Sahbaie P, Shi X, Guo TZ, Qiao Y, Yeomans DC, Kingery WS, Clark JD: Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision. Pain. 2009, 145: 341-349. 10.1016/j.pain.2009.06.037.PubMedCentralCrossRefPubMed

Title: Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitrostudy
Authors: Ya-Tin Lin
Long-Sun Ro
Hung-Li Wang
Jin-Chung Chen
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2011
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-8-126

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitrostudy

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

Increased local concentration of complement C5a contributes to incisional pain in mice

Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma

Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures

Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes

Poly(I:C) promotes TNFα/TNFR1-dependent oligodendrocyte death in mixed glial cultures

Neuropeptide Y inhibits interleukin-1β-induced phagocytosis by microglial cells