Peripheral Nerve Injury Modulates Neurotrophin Signaling in the Peripheral and Central Nervous System

Molecular Neurobiology

Volumn 50, Issue 3, 2014, Pages 945-970

  Richner, Mette ^a   Ulrichsen, Maj ^a   Elmegaard, Siri Lander ^a   Dieu, Ruthe ^a   Pallesen, Lone Tjener ^a   Vaegter, Christian Bjerggaard ^a  

^a AARHUS UNIVERSITY   (Denmark)

Author keywords

Neuropathic pain; Neurotrophins; Peripheral nerve injury; Regeneration

Indexed keywords

GROWTH FACTOR RECEPTOR; NERVE GROWTH FACTOR;

ANIMAL; CENTRAL NERVOUS SYSTEM; METABOLISM; PERIPHERAL NERVE INJURY; PERIPHERAL NERVOUS SYSTEM; SIGNAL TRANSDUCTION;

ANIMALS; CENTRAL NERVOUS SYSTEM; NERVE GROWTH FACTORS; PERIPHERAL NERVE INJURIES; PERIPHERAL NERVOUS SYSTEM; RECEPTORS, GROWTH FACTOR; SIGNAL TRANSDUCTION;

EID: 84936765097     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-014-8706-9     Document Type: Review

References (312)

1. Battiston B, Papalia I, Tos P, Geuna S (2009) Chapter 1: Peripheral nerve repair and regeneration research: a historical note. Int Rev Neurobiol 87:1–7. doi:10.1016/S0074-7742(09)87001-3
2. NIH Publication No. 04-4853 (Peripheral Neuropathy Fact Sheet)
3. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309. doi:10.1038/nrn1078
4. Kashiba H, Noguchi K, Ueda Y, Senba E (1995) Coexpression of trk family members and low-affinity neurotrophin receptors in rat dorsal root ganglion neurons. Brain Res Mol Brain Res 30:158–164
5. Wright DE, Snider WD (1995) Neurotrophin receptor mRNA expression defines distinct populations of neurons in rat dorsal root ganglia. J Comp Neurol 351:329–338
6. Bibel M, Hoppe E, Barde YA (1999) Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J 18:616–622. doi:10.1093/emboj/18.3.616
7. Benedetti M, Levi A, Chao MV (1993) Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness. Proc Natl Acad Sci U S A 90:7859–7863
8. Hempstead BL, Martin-Zanca D, Kaplan DR et al (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350:678–683. doi:10.1038/350678a0
9. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564. doi:10.1098/rstb.2006.1894
10. Nykjaer A, Lee R, Teng KK et al (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848. doi:10.1038/nature02319
11. Jansen P, Giehl K, Nyengaard JR et al (2007) Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci 10:1449–1457. doi:10.1038/nn2000
12. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science (New York, NY) 294:1945–1948. doi:10.1126/science.1065057
13. Masoudi R, Ioannou MS, Coughlin MD et al (2009) Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors. J Biol Chem 284:18424–18433. doi:10.1074/jbc.M109.007104
14. Teng HK, Teng KK, Lee R et al (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463. doi:10.1523/JNEUROSCI.5123-04.2005
15. Nikoletopoulou V, Lickert H, Frade JM et al (2010) Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467:59–63. doi:10.1038/nature09336
16. Martini FH (2005) Anatomy and physiology, 1st ed. Pearson Education, Inc
17. Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB (2011) The Spared Nerve Injury (SNI) model of induced mechanical allodynia in mice. J Vis Exp. doi:10.3791/3092
18. Rigaud M, Gemes G, Barabas M-E et al (2008) Species and strain differences in rodent sciatic nerve anatomy: implications for studies of neuropathic pain. Pain 136:188–201. doi:10.1016/j.pain.2008.01.016
19. Amir R, Devor M (2003) Electrical excitability of the soma of sensory neurons is required for spike invasion of the soma, but not for through-conduction. Biophys J 84:2181–2191
20. Huang L-YM, Gu Y, Chen Y (2013) Communication between neuronal somata and satellite glial cells in sensory ganglia. Glia 1–11. doi: 10.1002/glia.22541
21. Pannese E (2010) The structure of the perineuronal sheath of satellite glial cells (SGCs) in sensory ganglia. Neuron Glia Biol 6:3–10. doi:10.1017/S1740925X10000037
22. Pannese E, Ledda M, Arcidiacono G, Rigamonti L (1991) Clusters of nerve cell bodies enclosed within a common connective tissue envelope in the spinal ganglia of the lizard and rat. Cell Tissue Res 264:209–214
23. Pannese E (1981) The satellite cells of the sensory ganglia. Adv Anat Embryol Cell Biol 65:1–111
24. Hanani M (2005) Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 48:457–476. doi:10.1016/j.brainresrev.2004.09.001
25. Jessen KR, Mirsky R (2005) The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 6:671–682. doi:10.1038/nrn1746
26. Bear MF, Connors BW, Paradiso MA (2007) Neuroscience: exploring the brain, 3rd edn. Lippincott Williams & Wilkins, Baltimore, MD
27. Manzano GM, Giuliano LMP, Nóbrega JAM (2008) A brief historical note on the classification of nerve fibers. Arq Neuropsiquiatr 66:117–119
28. Lewin GR, Moshourab R (2004) Mechanosensation and pain. J Neurobiol 61:30–44. doi:10.1002/neu.20078
29. Lallemend F, Ernfors P (2012) Molecular interactions underlying the specification of sensory neurons. Trends Neurosci 35:373–381. doi:10.1016/j.tins.2012.03.006
30. Honma Y, Kawano M, Kohsaka S, Ogawa M (2010) Axonal projections of mechanoreceptive dorsal root ganglion neurons depend on Ret. Development (Cambridge, England) 137:2319–2328. doi:10.1242/dev.046995
31. Flemming W (1882) Flemming: Vom Bau der Spinalganglienzellen. Festschrift für Henle
32. Daae H (1887) Zur Kenntniss der Spinalganglienzellen beim Säugethier. Arch Mikrosk Anat 31:223–235. doi:10.1007/BF02955708
33. Müller E (1891) Untersuchungen über den Bau der Spinal-ganglien. Nordiskt Medicinskt Arkiv 23:1–55. doi:10.1111/j.0954-6820.1891.tb00764.x
34. Lawson SN (1979) The postnatal development of large light and small dark neurons in mouse dorsal root ganglia: a statistical analysis of cell numbers and size. J Neurocytol 8:275–294
35. Hossack J, Wyburn GM (1954) XVI.—Electron Microscopic Studies of Spinal Ganglion Cells. Proc R Soc Edinb B Biol 65:239–250. doi:10.1017/S0080455X00012133
36. Andres KH (1961) Untersuchungen über den Feinbau von Spinalganglien. Cell Tissue Res 55:1–48. doi:10.1007/BF00319327
37. Lawson SN, Harper AA, Harper EI et al (1984) A monoclonal antibody against neurofilament protein specifically labels a subpopulation of rat sensory neurones. J Comp Neurol 228:263–272. doi:10.1002/cne.902280211
38. Averill S, McMahon SB, Clary DO et al (1995) Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons. Eur J Neurosci 7:1484–1494. doi:10.1111/j.1460-9568.1995.tb01143.x
39. Priestley JV, Michael GJ, Averill S et al (2002) Regulation of nociceptive neurons by nerve growth factor and glial cell line derived neurotrophic factor. Can J Physiol Pharmacol 80:495–505. doi:10.1139/y02-034
40. Scott SA (1992) Sensory neurons: diversity, development, and plasticity. Oxford University Press
41. Price J (1985) An immunohistochemical and quantitative examination of dorsal root ganglion neuronal subpopulations. J Neurosci 5:2051–2059
42. Harper AA, Lawson SN (1985) Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurones. J Physiol Lond 359:31–46
43. Karchewski LA, Kim FA, Johnston J et al (1999) Anatomical evidence supporting the potential for modulation by multiple neurotrophins in the majority of adult lumbar sensory neurons. J Comp Neurol 413:327–341
44. Verge VM, Merlio JP, Grondin J et al (1992) Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF. J Neurosci 12:4011–4022
45. Verge VMK, Richardson PM, Benoit R, Riopelle RJ (1989) Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor. J Neurocytol 18:583–591. doi:10.1007/BF01187079
46. Mu X, Silos-Santiago I, Carroll SL, Snider WD (1993) Neurotrophin receptor genes are expressed in distinct patterns in developing dorsal root ganglia. J Neurosci 13:4029–4041
47. Bennett DLD, Averill SS, Clary DOD et al (1996) Postnatal changes in the expression of the trkA high-affinity NGF receptor in primary sensory neurons. Eur J Neurosci 8:2204–2208. doi:10.1111/j.1460-9568.1996.tb00742.x
48. McMahon SB, Armanini MP, Ling LH, Phillips HS (1994) Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 12:1161–1171
49. Molliver DC, Radeke MJ, Feinstein SC, Snider WD (1995) Presence or absence of TrKA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 361:404–416. doi:10.1002/cne.903610305
50. Smeyne RJ, Klein R, Schnapp A et al (1994) Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368:246–249. doi:10.1038/368246a0
51. Crowley C, Spencer SD, Nishimura MC et al (1994) Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001–1011
52. Stucky CL, Koltzenburg M, Schneider M et al (1999) Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors. J Neurosci 19:8509–8516
53. Wetmore C, Olson L (1995) Neuronal and nonneuronal expression of neurotrophins and their receptors in sensory and sympathetic ganglia suggest new intercellular trophic interactions. J Comp Neurol 353:143–159. doi:10.1002/cne.903530113
54. Michael GJG, Averill SS, Nitkunan AA et al (1997) 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 17:8476–8490
55. Snider WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638
56. Bennett DL, Michael GJ, Ramachandran N et al (1998) A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci 18:3059–3072
57. Snider WD, McMahon SB (1998) Tackling pain at the source: new ideas about nociceptors. Neuron 20:629–632
58. Light AR, Trevino DL, Perl ER (1979) Morphological features of functionally defined neurons in the marginal zone and substantia gelatinosa of the spinal dorsal horn. J Comp Neurol 186:151–171. doi:10.1002/cne.901860204
59. Malmberg AB (1997) Preserved acute pain and reduced neuropathic pain in mice lacking PKC. Science (New York, NY) 278:279–283. doi:10.1126/science.278.5336.279
60. Pannese E, Procacci P (2002) Ultrastructural localization of NGF receptors in satellite cells of the rat spinal ganglia. J Neurocytol 31:755–763. doi:10.1023/A:1025708132119
61. Kuo L-T, Groves MJ, Scaravilli F et al (2007) Neurotrophin-3 administration alters neurotrophin, neurotrophin receptor and nestin mRNA expression in rat dorsal root ganglia following axotomy. Neuroscience 147:491–507. doi:10.1016/j.neuroscience.2007.04.023
62. Zhou X-F, Chie ET, Deng YS et al (1999) Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat. Neuroscience 92:841–853
63. Zhou X-F, Deng YS, Chie E et al (1999) Satellite-cell-derived nerve growth factor and neurotrophin-3 are involved in noradrenergic sprouting in the dorsal root ganglia following peripheral nerve injury in the rat. Eur J Neurosci 11:1711–1722
64. van Velzen M, Laman JD, Kleinjan A et al (2009) Neuron-interacting satellite glial cells in human trigeminal ganglia have an APC phenotype. J Immunol 183:2456–2461. doi:10.4049/jimmunol.0900890
65. Geuna S, Raimondo S, Ronchi G et al (2009) Chapter 3: Histology of the peripheral nerve and changes occurring during nerve regeneration. Int Rev Neurobiol 87:27–46. doi:10.1016/S0074-7742(09)87003-7
66. Geuna S, Fornaro M, Raimondo S, Giacobini-Robecchi MG (2010) Plasticity and regeneration in the peripheral nervous system. Ital J Anat Embryol 115:91–94
67. Huang T-Y, Belzer V, Hanani M (2010) Gap junctions in dorsal root ganglia: possible contribution to visceral pain. Eur J Pain 14(49):e1–11. doi:10.1016/j.ejpain.2009.02.005
68. Ramer MS, Bradbury EJ (2001) Nerve growth factor induces P2X3 expression in sensory neurons. J Neurochem 77:864–875
69. Hanani M, Huang TY, Cherkas PS et al (2002) Glial cell plasticity in sensory ganglia induced by nerve damage. Neuroscience 114:279–283
70. Pannese E, Ledda M, Cherkas PS et al (2003) Satellite cell reactions to axon injury of sensory ganglion neurons: increase in number of gap junctions and formation of bridges connecting previously separate perineuronal sheaths. Anat Embryol 206:337–347. doi:10.1007/s00429-002-0301-6
71. Bergman E, Fundin BT, Ulfhake B (1999) Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons. J Comp Neurol 410:368–386
72. Obata K, Katsura H, Sakurai J et al (2006) Suppression of the p75 neurotrophin receptor in uninjured sensory neurons reduces neuropathic pain after nerve injury. J Neurosci 26:11974–11986. doi:10.1523/JNEUROSCI.3188-06.2006
73. Apfel SC, Wright DE, Wiideman AM et al (1996) Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system. Mol Cell Neurosci 7:134–142. doi:10.1006/mcne.1996.0010
74. Cho HJH, Kim JKJ, Park HCH et al (1998) Changes in brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia, spinal cord, and gracile nuclei following cut or crush injuries. Exp Neurol 154:7–7. doi:10.1006/exnr.1998.6936
75. Fukuoka T, Kondo E, Dai Y et al (2001) Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21:4891–4900
76. Mannion RJ, Costigan M, Decosterd I et al (1999) Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A 96:9385–9390. doi:10.1073/pnas.96.16.9385
77. Bennett DL (2001) Neurotrophic factors: important regulators of nociceptive function. Neuroscientist 7:13–17
78. Pezet S, Malcangio M, Lever IJ et al (2002) Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol Cell Neurosci 21:684–695
79. McMahon SBS, Jones NGN (2004) Plasticity of pain signaling: role of neurotrophic factors exemplified by acid-induced pain. J Neurobiol 61:72–87. doi:10.1002/neu.20093
80. Ha SOS, Kim JKJ, Hong HSH et al (2000) 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
81. Ramer MS, Thompson SW, McMahon SB (1999) Causes and consequences of sympathetic basket formation in dorsal root ganglia. Pain Suppl 6:S111–20
82. Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29:507–538. doi:10.1146/annurev.neuro.29.051605.112929
83. Cajal SRY (1928) Degeneration and regeneration of the nervous system. Oxford University Press, Oxford
84. Munson JB, Shelton DL, McMahon SB (1997) Adult mammalian sensory and motor neurons: roles of endogenous neurotrophins and rescue by exogenous neurotrophins after axotomy. J Neurosci 17:470–476
85. Kurata S, Goto T, Gunjigake KK et al (2013) Nerve growth factor involves mutual interaction between neurons and satellite glial cells in the rat trigeminal ganglion. Acta Histochem Cytochem 46:65–73. doi:10.1267/ahc.13003
86. Castillo C, Norcini M, Martin Hernandez LA et al (2013) Satellite glia cells in dorsal root ganglia express functional NMDA receptors. Neuroscience 240C:135–146. doi:10.1016/j.neuroscience.2013.02.031
87. Dublin P, Hanani M (2007) Satellite glial cells in sensory ganglia: their possible contribution to inflammatory pain. Brain Behav Immun 21:592–598. doi:10.1016/j.bbi.2006.11.011
88. Ohara PT, Vit J-P, Bhargava A et al (2009) Gliopathic pain: when satellite glial cells go bad. Neuroscientist 15:450–463. doi:10.1177/1073858409336094
89. Jasmin L, Vit J-P, Bhargava A, Ohara PT (2010) Can satellite glial cells be therapeutic targets for pain control? Neuron Glia Biol 6:63–71. doi:10.1017/S1740925X10000098
90. Qiao L-YL, Vizzard MAM (2005) Spinal cord injury-induced expression of TrkA, TrkB, phosphorylated CREB, and c-Jun in rat lumbosacral dorsal root ganglia. J Comp Neurol 482:142–154. doi:10.1002/cne.20394
91. Miller FD, Speelman A, Mathew TC et al (1994) Nerve growth factor derived from terminals selectively increases the ratio of p75 to trkA NGF receptors on mature sympathetic neurons. Dev Biol 161:206–217. doi:10.1006/dbio.1994.1021
92. Belliveau DJ (1997) NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis. J Cell Biol 136:375–388. doi:10.1083/jcb.136.2.375
93. Zhou X-F, Rush RA, McLachlan EM (1996) Differential expression of the p75 nerve growth factor receptor in glia and neurons of the rat dorsal root ganglia after peripheral nerve transection. J Neurosci 16:2901–2911
94. Ramer M, Bisby M (1997) Reduced sympathetic sprouting occurs in dorsal root ganglia after axotomy in mice lacking low-affinity neurotrophin receptor. Neurosci Lett 228:9–12
95. Otto DD, Unsicker KK, Grothe CC (1987) Pharmacological effects of nerve growth factor and fibroblast growth factor applied to the transectioned sciatic nerve on neuron death in adult rat dorsal root ganglia. Neurosci Lett 83:156–160
96. Cheema SS, Barrett GL, Bartlett PF (1996) Reducing p75 nerve growth factor receptor levels using antisense oligonucleotides prevents the loss of axotomized sensory neurons in the dorsal root ganglia of newborn rats. J Neurosci Res 46:239–245. doi:10.1002/(SICI)1097-4547(19961015)46:2<239::AID-JNR12>3.0.CO;2-Y
97. Vestergaard S, Tandrup T, Jakobsen J (1997) Effect of permanent axotomy on number and volume of dorsal root ganglion cell bodies. J Comp Neurol 388:307–312
98. Degn J, Tandrup T, Jakobsen J (1999) Effect of nerve crush on perikaryal number and volume of neurons in adult rat dorsal root ganglion. J Comp Neurol 412:186–192. doi:10.1002/(SICI)1096-9861(19990913)412:1<186::AID-CNE14>3.0.CO;2-H
99. Shi TJ, Tandrup T, Bergman E et al (2001) Effect of peripheral nerve injury on dorsal root ganglion neurons in the C57 BL/6 J mouse: marked changes both in cell numbers and neuropeptide expression. Neuroscience 105:249–263
100. Gjerstad MD, Tandrup T, Koltzenburg M, Jakobsen J (2002) Predominant neuronal B-cell loss in L5 DRG of p75 receptor-deficient mice. J Anat 200:81–87
101. Sørensen B, Tandrup T, Koltzenburg M, Jakobsen J (2003) No further loss of dorsal root ganglion cells after axotomy in p75 neurotrophin receptor knockout mice. J Comp Neurol 459:242–250. doi:10.1002/cne.10625
102. Zhou X-F, Li W-P, Zhou FH-H et al (2005) Differential effects of endogenous brain-derived neurotrophic factor on the survival of axotomized sensory neurons in dorsal root ganglia: a possible role for the p75 neurotrophin receptor. Neuroscience 132:591–603. doi:10.1016/j.neuroscience.2004.12.034
103. Jiang Y, Zhang JS, Jakobsen J (2005) Differential effect of p75 neurotrophin receptor on expression of pro-apoptotic proteins c-jun, p38 and caspase-3 in dorsal root ganglion cells after axotomy in experimental diabetes. Neuroscience 132:1083–1092. doi:10.1016/j.neuroscience.2005.01.049
104. Jiang Y, Jakobsen J (2010) Different apoptotic reactions of dorsal root ganglion A- and B-cells after sciatic nerve axotomy: effect of p75 neurotrophin receptor. Chin Med J 123:2695–2700
105. Arnett MG, Ryals JM, Wright DE (2007) Pro-NGF, sortilin, and p75NTR: potential mediators of injury-induced apoptosis in the mouse dorsal root ganglion. Brain Res Rev 1183:32–42. doi:10.1016/j.brainres.2007.09.051
106. Vaegter CB, Jansen P, Fjorback AW et al (2011) Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci 14:54–61. doi:10.1038/nn.2689
107. Averill SS, Michael GJG, Shortland PJP et al (2004) NGF and GDNF ameliorate the increase in ATF3 expression which occurs in dorsal root ganglion cells in response to peripheral nerve injury. Eur J Neurosci 19:1437–1445. doi:10.1111/j.1460-9568.2004.03241.x
108. Zwick M, Davis BM, Woodbury CJ et al (2002) Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci 22:4057–4065
109. Obata KK, Yamanaka HH, Kobayashi KK et al (2004) 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 24:10211–10222. doi:10.1523/JNEUROSCI.3388-04.2004
110. Obata K, Yamanaka H, Dai Y et al (2004) Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci 20:2881–2895. doi:10.1111/j.1460-9568.2004.03754.x
111. Bergmann I, Reiter R, Toyka KV, Koltzenburg M (1998) Nerve growth factor evokes hyperalgesia in mice lacking the low-affinity neurotrophin receptor p75. Neurosci Lett 255:87–90
112. Chuang HH, Prescott ED, Kong H et al (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962. doi:10.1038/35082088
113. Bonnington JKJ, McNaughton PAP (2003) Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol 551:433–446. doi:10.1113/jphysiol.2003.039990
114. Kobayashi K, Fukuoka T, Obata K et al (2005) Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol 493:596–606. doi:10.1002/cne.20794
115. Ji R-R, Samad TA, Jin S-X et al (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68
116. Bron R, Klesse LJ, Shah K et al (2003) Activation of Ras is necessary and sufficient for upregulation of vanilloid receptor type 1 in sensory neurons by neurotrophic factors. Mol Cell Neurosci 22:118–132
117. Kerr BJ, Souslova V, McMahon SB, Wood JN (2001) A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain. Neuroreport 12:3077–3080
118. Mamet J, Lazdunski M, Voilley N (2003) How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. J Biol Chem 278:48907–48913. doi:10.1074/jbc.M309468200
119. Mantyh PW, Koltzenburg M, Mendell LM et al (2011) Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 115:189–204. doi:10.1097/ALN.0b013e31821b1ac5
120. Thomas PK, Berthold CH, Ochoa J (1993) Microscopic anatomy of the peripheral nervous system. In: Peripheral neuropathy, 3rd ed. WB Saunders, Philadelphia, PA, pp 28–92
121. Key A, Retzius G (1876) Studien der Anatomie des Nervensystems und des Bindegewebes. Samson & Wallin
122. Akert K, Sandri C, Weibel ER et al (1976) The fine structure of the perineural endothelium. Cell Tissue Res 165:281–295
123. Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflamm 8:110. doi:10.1523/JNEUROSCI.2269-10.2010
124. Lubińska L (1982) Patterns of Wallerian degeneration of myelinated fibres in short and long peripheral stumps and in isolated segments of rat phrenic nerve. Interpretation of the role of axoplasmic flow of the trophic factor. Brain Res Rev 233:227–240
125. Schlaepfer WW (1977) Structural alterations of peripheral nerve induced by the calcium ionophore A23187. Brain Res Rev 136:1–9
126. Vial JD (1958) The early changes in the axoplasm during Wallerian degeneration. J Biophys Biochem Cytol 4:551–555
127. Ghabriel MN, Allt G (1979) The role of Schmidt–Lanterman incisures in Wallerian degeneration: II. An electron microscopic study. Acta Neuropathol 48:95–103
128. Yao D, Li M, Shen D et al (2013) Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat. Neurosci Bull 29:321–332. doi:10.1007/s12264-013-1340-0
129. Funakoshi H, Risling M, Carlstedt T, et al. (1998) Targeted expression of a multifunctional chimeric neurotrophin in the lesioned sciatic nerve accelerates regeneration of sensory and motor axons. 95:5269–5274
130. Funakoshi H, Frisén J, Barbany G et al (1993) Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 123:455–465
131. Heumann R, Lindholm D, Bandtlow C et al (1987) Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc Natl Acad Sci U S A 84:8735–8739
132. Thoenen H, Bandtlow C, Heumann R et al (1988) Nerve growth factor: cellular localization and regulation of synthesis. Cell Mol Neurobiol 8:35–40
133. Warner LE, Mancias P, Butler IJ et al (1998) Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 18:382–384. doi:10.1038/ng0498-382
134. Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56:1552–1565. doi:10.1002/glia.20761
135. Fontana X, Hristova M, Da Costa C et al (2012) c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling. J Cell Biol 198:127–141. doi:10.1083/jcb.201205025
136. Kim CF, Moalem-Taylor G (2011) Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res Rev 1405:95–108. doi:10.1016/j.brainres.2011.06.022
137. Shubayev VI, Angert M, Dolkas J et al (2006) TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci 31:407–415. doi:10.1016/j.mcn.2005.10.011
138. Dubový P (2011) Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction. Ann Anat 193:267–275. doi:10.1016/j.aanat.2011.02.011
139. Chen Z-L, Yu W-M, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–33. doi:10.1146/annurev.neuro.30.051606.094337
140. Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14:67–116. doi:10.1007/BF02740621
141. Sunderland S (1952) Factors influencing the course of regeneration and the quality of the recovery after nerve suture. Brain 75:19–54
142. Ernfors P, Lee K-F, Jaenisch R (1994) Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368:147–150. doi:10.1038/368147a0
143. Fariñas I, Jones KR, Backus C et al (1994) Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature 369:658–661. doi:10.1038/369658a0
144. Yan Q, Elliott J, Snider WD (1992) Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360:753–5. doi:10.1038/360753a0
145. Sendtner M, Holtmann B, Kolbeck R et al (1992) Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 360:757–759. doi:10.1038/360757a0
146. Koliatsos VE, Clatterbuck RE, Winslow JW et al (1993) Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron 10:359–367
147. Funakoshi H, Belluardo N, Arenas E, et al. (1995) Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science (New York, NY) 268:1495–1499
148. Meyer M, Matsuoka I, Wetmore C et al (1992) 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
149. Zhang JYJ, Luo XGX, Xian CJC et al (2000) Endogenous BDNF is required for myelination and regeneration of injured sciatic nerve in rodents. Eur J Neurosci 12:4171–4180. doi:10.1111/j.1460-9568.2000.01312.x
150. Acheson A, Barker PA, Alderson RF et al (1991) Detection of brain-derived neurotrophic factor-like activity in fibroblasts and Schwann cells: inhibition by antibodies to NGF. Neuron 7:265–275
151. Zhou X-F, Rush RA (1996) Endogenous brain-derived neurotrophic factor is anterogradely transported in primary sensory neurons. Neuroscience 74:945–953
152. Tonra JR, Curtis R, Wong V et al (1998) Axotomy upregulates the anterograde transport and expression of brain-derived neurotrophic factor by sensory neurons. J Neurosci 18:4374–4383
153. Korte M, Carroll P, Wolf E et al (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856–8860
154. English AW, Meador W, Carrasco DI (2005) Neurotrophin-4/5 is required for the early growth of regenerating axons in peripheral nerves. Eur J Neurosci 21:2624–2634. doi:10.1111/j.1460-9568.2005.04124.x
155. Boyd JG, Gordon T (2002) A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci 15:613–626
156. Fu SY, Gordon T (1995) Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci 15:3886–3895
157. Wood SJ, Pritchard J, Sofroniew MV (1989) Re-expression of nerve growth factor receptor after axonal injury recapitulates a developmental event in motor neurons: differential regulation when regeneration is allowed or prevented. Eur J Neurosci 2:650–657. doi:10.1111/j.1460-9568.1990.tb00454.x
158. Ernfors P, Henschen A, Olson L, Persson H (1989) Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2:1605–1613
159. Bussmann KAV, Sofroniew MV (1999) Re-expression of p75NTR by adult motor neurons after axotomy is triggered by retrograde transport of a positive signal from axons regrowing through damaged or denervated peripheral nerve tissue. Neuroscience 91:273–281. doi:10.1016/S0306-4522(98)00562-4
160. Taniuchi M, Clark HB, Schweitzer JB, Johnson EM Jr (1988) Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J Neurosci 8:664–681
161. Taniuchi M, Clark HB, Johnson EM Jr (1986) Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc Natl Acad Sci U S A 83:4094–4098
162. Tomita K, Kubo T, Matsuda K et al (2007) The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury. Glia 55:1199–1208. doi:10.1002/glia.20533
163. Wilhelm JC, Xu M, Cucoranu D et al (2012) Cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration. J Neurosci 32:5002–5009. doi:10.1523/JNEUROSCI.1411-11.2012
164. Geremia NM, Pettersson LME, Hasmatali JC et al (2010) Endogenous BDNF regulates induction of intrinsic neuronal growth programs in injured sensory neurons. Exp Neurol 223:128–142. doi:10.1016/j.expneurol.2009.07.022
165. Sun Y, Lim Y, Li F et al (2012) ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLoS ONE 7:e35883. doi:10.1371/journal.pone.0035883
166. Heumann R, Korsching S, Bandtlow C, Thoenen H (1987) Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J Cell Biol 104:1623–1631
167. Lindholm D, Heumann R, Meyer M, Thoenen H (1987) Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature 330:658–659. doi:10.1038/330658a0
168. Johnson EM Jr, Taniuchi M, DiStefano PS (1988) Expression and possible function of nerve growth factor receptors on Schwann cells. Trends Neurosci 11:299–304
169. Diamond J, Foerster A, Holmes M, Coughlin M (1992) Sensory nerves in adult rats regenerate and restore sensory function to the skin independently of endogenous NGF. J Neurosci 12:1467–1476
170. Meier C, Parmantier E, Brennan A et al (1999) Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB. J Neurosci 19:3847–3859
171. Sahenk Z, Oblinger J, Edwards C (2008) Neurotrophin-3 deficient Schwann cells impair nerve regeneration. Exp Neurol 212:552–6. doi:10.1016/j.expneurol.2008.04.015
172. Li H, Terenghi G, Hall SM (1997) Effects of delayed re-innervation on the expression of c-erbB receptors by chronically denervated rat Schwann cells in vivo. Glia 20:333–347
173. Sulaiman OA, Gordon T (2000) Effects of short- and long-term Schwann cell denervation on peripheral nerve regeneration, myelination, and size. Glia 32:234–246. doi:10.1002/1098-1136(200012)32:3<234::AID-GLIA40>3.0.CO;2-3
174. Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H (1995) Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J Neurosci Res 42:21–33. doi:10.1002/jnr.490420104
175. Yin Q, kemp GJ, Yu L-G (2001) Neurotrophin-4 delivered by fibrin glue promotes peripheral nerve regeneration. Muscle Nerve 24:345–351. doi:10.1002/1097-4598(200103)24:3<345::AID-MUS1004>3.0.CO;2-P
176. Jessen KR, Mirsky R (2002) Signals that determine Schwann cell identity. J Anat 200:367–376
177. Höke A (2006) Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J Neurosci 26:9646–9655. doi:10.1523/JNEUROSCI.1620-06.2006
178. Brushart TM, Aspalter M, Griffin JW et al (2013) Schwann cell phenotype is regulated by axon modality and central–peripheral location, and persists in vitro. Exp Neurol 247:272–281. doi:10.1016/j.expneurol.2013.05.007
179. Meyer zu Hörste G, Prukop T, Nave K-A, Sereda MW (2006) Myelin disorders: causes and perspectives of Charcot–Marie–Tooth neuropathy. J Mol Neurosci 28:77–88
180. Tzakos AG, Troganis A, Theodorou V et al (2005) Structure and function of the myelin proteins: current status and perspectives in relation to multiple sclerosis. Curr Med Chem 12:1569–1587
181. Bunge MB, Williams AK, Wood PM (1982) Neuron–Schwann cell interaction in basal lamina formation. Dev Biol 92:449–460
182. Yamauchi J, Chan JR, Shooter EM (2003) Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proc Natl Acad Sci U S A 100:14421–14426. doi:10.1073/pnas.2336152100
183. Yamauchi J, Chan JR, Shooter EM (2004) Neurotrophins regulate Schwann cell migration by activating divergent signaling pathways dependent on Rho GTPases. Proc Natl Acad Sci U S A 101:8774–8779. doi:10.1073/pnas.0402795101
184. Anton ES, Weskamp G, Reichardt LF, Matthew WD (1994) Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc Natl Acad Sci U S A 91:2795–2799
185. Bentley CA, Lee KF (2000) p75 is important for axon growth and Schwann cell migration during development. J Neurosci 20:7706–7715
186. Chan JR, Watkins TA, Cosgaya JM et al (2004) NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43:183–191
187. Chan JR, Cosgaya JM, Wu YJ, Shooter EM (2001) Neurotrophins are key mediators of the myelination program in the peripheral nervous system. Proc Natl Acad Sci U S A 98:14661–14668. doi:10.1073/pnas.251543398
188. Ng BK, Chen L, Mandemakers W et al (2007) Anterograde transport and secretion of brain-derived neurotrophic factor along sensory axons promote Schwann cell myelination. J Neurosci 27:7597–7603. doi:10.1523/JNEUROSCI.0563-07.2007
189. Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science (New York, NY) 298:1245–1248. doi:10.1126/science.1076595
190. Song X-Y, Zhou FH-H, Zhong J-H et al (2006) Knockout of p75NTR impairs re-myelination of injured sciatic nerve in mice. J Neurochem 96:833–842. doi:10.1111/j.1471-4159.2005.03564.x
191. Kemp SWP, Webb AA, Dhaliwal S et al (2011) Dose and duration of nerve growth factor (NGF) administration determine the extent of behavioral recovery following peripheral nerve injury in the rat. Exp Neurol 229:460–470. doi:10.1016/j.expneurol.2011.03.017
192. Jubran M, Widenfalk J (2003) Repair of peripheral nerve transections with fibrin sealant containing neurotrophic factors. Exp Neurol 181:204–212
193. Tannemaat MR, Boer GJ, Verhaagen J, Malessy MJA (2007) Genetic modification of human surel nerve segments by a lentiviral vector encoding nerve growth factor. Neurosurgery 61:1286–1296. doi:10.1227/01.neu.0000306108.78044.a2
194. Tannemaat MR, Eggers R, Hendriks WT et al (2008) Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve. Eur J Neurosci 28:1467–1479. doi:10.1111/j.1460-9568.2008.06452.x
195. Hu X, Cai J, Yang J, Smith GM (2010) Sensory axon targeting is increased by NGF gene therapy within the lesioned adult femoral nerve. Exp Neurol 223:153–165. doi:10.1016/j.expneurol.2009.08.025
196. de Boer R, Knight AM, Borntraeger A et al (2011) Rat sciatic nerve repair with a poly-lactic-co-glycolic acid scaffold and nerve growth factor releasing microspheres. Microsurgery 31:293–302. doi:10.1002/micr.20869
197. Chung T-W, Yang M-C, Tseng C-C et al (2011) Promoting regeneration of peripheral nerves in-vivo using new PCL-NGF/Tirofiban nerve conduits. Biomaterials 32:734–743. doi:10.1016/j.biomaterials.2010.09.023
198. Yan Q, Yin Y, Li B (2012) Use new PLGL-RGD-NGF nerve conduits for promoting peripheral nerve regeneration. Biomed Eng Online 11:36. doi:10.1186/1475-925X-11-36
199. Shakhbazau A, Kawasoe J, Hoyng SA et al (2012) Early regenerative effects of NGF-transduced Schwann cells in peripheral nerve repair. Mol Cell Neurosci 50:103–112. doi:10.1016/j.mcn.2012.04.004
200. Sahenk Z, Nagaraja HN, McCracken BS et al (2005) NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology 65:681–689. doi:10.1212/01.wnl.0000171978.70849.c5
201. Godinho MJ, Teh L, Pollett MA et al (2012) Immunohistochemical, ultrastructural and functional analysis of axonal regeneration through peripheral nerve grafts containing Schwann cells expressing BDNF, CNTF or NT3. PLoS ONE 8:e69987–e69987. doi:10.1371/journal.pone.0069987
202. Gordon T, Sulaiman O, Boyd JG (2003) Experimental strategies to promote functional recovery after peripheral nerve injuries. J Peripher Nerv Syst 8:236–250
203. English AW, Schwartz G, Meador W et al (2007) Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling. Dev Neurobiol 67:158–172. doi:10.1002/dneu.20339
204. Nadim W, Anderson PN, Turmaine M (1990) The role of Schwann cells and basal lamina tubes in the regeneration of axons through long lengths of freeze-killed nerve grafts. Neuropathol Appl Neurobiol 16:411–421
205. Krekoski CA, Neubauer D, Zuo J, Muir D (2001) Axonal regeneration into acellular nerve grafts is enhanced by degradation of chondroitin sulfate proteoglycan. J Neurosci 21:6206–6213
206. Al-Majed AA, Brushart TM, Gordon T (2000) Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. Eur J Neurosci 12:4381–4390
207. Geremia NM, Gordon T, Brushart TM et al (2007) Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression. Exp Neurol 205:347–359. doi:10.1016/j.expneurol.2007.01.040
208. Al-Majed AA, Tam SL, Gordon T (2004) Electrical stimulation accelerates and enhances expression of regeneration-associated genes in regenerating rat femoral motoneurons. Cell Mol Neurobiol 24:379–402
209. Sabatier MJ, Redmon N, Schwartz G, English AW (2008) Treadmill training promotes axon regeneration in injured peripheral nerves. Exp Neurol 211:489–493. doi:10.1016/j.expneurol.2008.02.013
210. English AW, Cucoranu D, Mulligan A, Sabatier M (2009) Treadmill training enhances axon regeneration in injured mouse peripheral nerves without increased loss of topographic specificity. J Comp Neurol 517:245–255. doi:10.1002/cne.22149
211. English AW, Cucoranu D, Mulligan A et al (2011) Neurotrophin-4/5 is implicated in the enhancement of axon regeneration produced by treadmill training following peripheral nerve injury. Eur J Neurosci 33:2265–2271. doi:10.1111/j.1460-9568.2011.07724.x
212. Buck CR, Seburn KL, Cope TC (2000) Neurotrophin expression by spinal motoneurons in adult and developing rats. J Comp Neurol 416:309–318
213. Frisén J, Verge VM, Fried K et al (1993) Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous systems. Proc Natl Acad Sci U S A 90:4971–4975
214. Gordon T (2009) The role of neurotrophic factors in nerve regeneration. J Neurosurg 26:E3. doi:10.3171/FOC.2009.26.2.E3
215. Jang S-W, Liu X, Yepes M et al (2010) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107:2687–2692. doi:10.1073/pnas.0913572107
216. Jang S-W, Liu X, Chan CB et al (2010) Deoxygedunin, a natural product with potent neurotrophic activity in mice. PLoS ONE 5:e11528. doi:10.1371/journal.pone.0011528
217. English AW, Liu K, Nicolini JM, et al. (2013) Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves. Proc Natl Acad Sci USA 1–6. doi: 10.1073/pnas.1303646110
218. Yaksh TL (1999) Spinal drug delivery. Elsevier Health Sciences
219. Cook MJ (1965) The anatomy of the laboratory mouse. Academic Press
220. Green EL (1962) Quantitative genetics of skeletal variations in the mouse: II. Crosses between four inbred strains (C3H, DBA, C57BL, BALB/c). Genetics 47:1085–1096
221. Green EL (1941) Genetic and non-genetic factors which influence the type of the skeleton in an inbred strain of mice. Genetics 26:192–222
222. Hankenson FC, Garzel LM, Fischer DD et al (2008) Evaluation of tail biopsy collection in laboratory mice (Mus musculus): vertebral ossification, DNA quantity, and acute behavioral responses. J Am Assoc Lab Anim Sci JAALAS 47:10–18
223. Shinohara H (1999) The mouse vertebrae: changes in the morphology of mouse vertebrae exhibit specific patterns over limited numbers of vertebral levels. Okajimas Folia Anat Japonica 76:17–31
224. Sakla FB (1969) Quantitative studies on the postnatal growth of the spinal cord and the vertebral column of the albino mouse. J Comp Neurol 136:237–247. doi:10.1002/cne.901360209
225. Watson C, Paxinos G, Kayalioglu G (2009) The spinal cord. Academic Press
226. Biscoe TJ, Nickels SM, Stirling CA (1982) Numbers and sizes of nerve fibres in mouse spinal roots. Q J Exp Physiol (Cambridge, England) 67:473–494
227. Altman J, Bayer SA (1984) The development of the rat spinal cord. Adv Anat Embryol Cell Biol 85:1–164
228. Rexed B (1952) The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol 96:414–495
229. Molander C, Xu Q, Grant G (1984) The cytoarchitectonic organization of the spinal cord in the rat: I. The lower thoracic and lumbosacral cord. J Comp Neurol 230:133–141. doi:10.1002/cne.902300112
230. Caspary T, Anderson KV (2003) Patterning cell types in the dorsal spinal cord: what the mouse mutants say. Nat Rev Neurosci 4:289–297. doi:10.1038/nrn1073
231. Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836. doi:10.1038/nrn2947
232. Ferri CC, Moore FA, Bisby MA (1998) Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor. J Neurobiol 34:1–9
233. Casaccia-Bonnefil P, Carter BD, Dobrowsky RT, Chao MV (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383:716–719. doi:10.1038/383716a0
234. Beattie MS, Harrington AW, Lee R et al (2002) ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36:375–386
235. Michael GJ, Kaya E, Averill S et al (1997) TrkA immunoreactive neurones in the rat spinal cord. J Comp Neurol 385:441–455
236. Ramer MS, Bradbury EJ, McMahon SB (2001) Nerve growth factor induces P2X(3) expression in sensory neurons. J Neurochem 77:864–875. doi:10.1046/j.1471-4159.2001.00288.x
237. Scarisbrick IA, Isackson PJ, Windebank AJ (1999) Differential expression of brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the adult rat spinal cord: regulation by the glutamate receptor agonist kainic acid. J Neurosci 19:7757–7769
238. Yan Q, Radeke MJ, Matheson CR et al (1997) Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J Comp Neurol 378:135–157
239. Merlio JP, Ernfors P, Jaber M, Persson H (1992) Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience 51:513–532
240. Zhou L-J, Yang T, Wei X et al (2011) Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun 25:322–334. doi:10.1016/j.bbi.2010.09.025
241. Thompson SW, Bennett DL, Kerr BJ et al (1999) Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci U S A 96:7714–7718
242. Miletic G, Miletic V (2002) 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
243. McMahon SB, Cafferty W (2004) Neurotrophic influences on neuropathic pain. Novartis Found Symp 261:68–102
244. Yajima Y, Narita M, Narita M et al (2002) 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 Rev 958:338–346
245. Wang X, Ratnam J, Zou B et al (2009) TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain. J Neurosci 29:5508–5515. doi:10.1523/JNEUROSCI.4288-08.2009
246. Michael GJ, Averill S, Shortland PJ et al (1999) 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
247. Li L, Xian CJ, Zhong J-H, Zhou X-F (2006) Upregulation of brain-derived neurotrophic factor in the sensory pathway by selective motor nerve injury in adult rats. Neurotox Res 9:269–283
248. Slack SE, Grist J, Mac Q et al (2005) TrkB expression and phospho-ERK activation by brain-derived neurotrophic factor in rat spinothalamic tract neurons. J Comp Neurol 489:59–68. doi:10.1002/cne.20606
249. Matsumoto T, Rauskolb S, Polack M et al (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11:131–133. doi:10.1038/nn2038
250. Srinivasan B, Roque CH, Hempstead BL et al (2004) Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor. J Biol Chem 279:41839–41845. doi:10.1074/jbc.M402872200
251. Ulmann L, Hatcher JP, Hughes JP et al (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J Neurosci 28:11263–11268. doi:10.1523/JNEUROSCI.2308-08.2008
252. Middlemas DS, Lindberg RA, Hunter T (1991) trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 11:143–153
253. Biffo S, Offenhauser N, Carter BD, Barde YA (1995) Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development (Cambridge, England) 121:2461–2470
254. Eide FF, Vining ER, Eide BL et al (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123–3129
255. Saarelainen T, Pussinen R, Koponen E et al (2000) Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP. Synapse (New York, NY) 38:102–104. doi:10.1002/1098-2396(200010)38:1<102::AID-SYN11>3.0.CO;2-K
256. Luikart BW, Nef S, Shipman T, Parada LF (2003) In vivo role of truncated trkb receptors during sensory ganglion neurogenesis. Neuroscience 117:847–858
257. Dorsey SG, Renn CL, Carim-Todd L et al (2006) In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron 51:21–28. doi:10.1016/j.neuron.2006.06.009
258. Carim-Todd L, Bath KG, Fulgenzi G et al (2009) Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo. J Neurosci 29:678–685. doi:10.1523/JNEUROSCI.5060-08.2009
259. Baxter GT, Radeke MJ, Kuo RC et al (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17:2683–2690
260. Yacoubian TA, Lo DC (2000) Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci 3:342–349. doi:10.1038/73911
261. Renn CL, Leitch CC, Dorsey SG (2009) In vivo evidence that truncated trkB.T1 participates in nociception. Mol Pain 5:61
262. Rose CR, Blum R, Pichler B et al (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426:74–78. doi:10.1038/nature01983
263. Dreyfus CF, Dai X, Lercher LD et al (1999) Expression of neurotrophins in the adult spinal cord in vivo. J Neurosci Res 56:1–7. doi:10.1002/(SICI)1097-4547(19990401)56:1<1::AID-JNR1>3.0.CO;2-3
264. Woolf CJ, Ma Q (2007) Nociceptors—noxious stimulus detectors. Neuron 55:353–364. doi:10.1016/j.neuron.2007.07.016
265. Whiteside GT, Munglani R (2001) Cell death in the superficial dorsal horn in a model of neuropathic pain. J Neurosci Res 64:168–173
266. Scholz J, Broom DC, Youn D-H et al (2005) Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 25:7317–7323. doi:10.1523/JNEUROSCI.1526-05.2005
267. Torsney C, MacDermott AB (2006) Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 26:1833–1843. doi:10.1523/JNEUROSCI.4584-05.2006
268. Hathway GJ, Vega-Avelaira D, Moss A et al (2009) Brief, low frequency stimulation of rat peripheral C-fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates. Pain 144:110–118. doi:10.1016/j.pain.2009.03.022
269. Suter MR, Berta T, Gao Y-J et al (2009) Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury. Mol Pain 5:53. doi:10.1186/1744-8069-5-53
270. Calvo M, Bennett DLH (2012) The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol 234:271–282. doi:10.1016/j.expneurol.2011.08.018
271. Tsuda M, Shigemoto-Mogami Y, Koizumi S et al (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783. doi:10.1038/nature01786
272. Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science (New York, NY) 330:841–5. doi:10.1126/science.1194637
273. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. doi:10.1146/annurev.immunol.021908.132528
274. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313. doi:10.1002/jnr.20562
275. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science (New York, NY) 308:1314–1318. doi:10.1126/science.1110647
276. White FA, Jung H, Miller RJ (2007) Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 14:20151–20158
277. Beggs S, Trang T, Salter MW (2012) P2X4R(+) microglia drive neuropathic pain. Nat Neurosci 15:1068–1073. doi:10.1038/nn.3155
278. Martin S, Vincent J-P, Mazella J (2003) Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci 23:1198–1205
279. Dicou E, Vincent J-P, Mazella J (2004) Neurotensin receptor-3/sortilin mediates neurotensin-induced cytokine/chemokine expression in a murine microglial cell line. J Neurosci Res 78:92–99. doi:10.1002/jnr.20231
280. Eriksson NP, Persson JK, Svensson M et al (1993) A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat. Exp Brain Res 96:19–27
281. Beggs S, Salter MW (2007) Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury. Brain Behav Immun 21:624–633. doi:10.1016/j.bbi.2006.10.017
282. Coyle DE (1998) Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23:75–83
283. Zhang F, Vadakkan KI, Kim SS et al (2008) Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse. Mol Pain. doi:10.1186/1744-8069-4-15
284. Tsuda M, Kuboyama K, Inoue T et al (2009) Behavioral phenotypes of mice lacking purinergic P2X. Mol Pain. doi:10.1186/1744-8069-5-28
285. Bennett MVL, Garré JM, Orellana JA et al (2012) Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res Rev 1487:3–15. doi:10.1016/j.brainres.2012.08.042
286. Foley JC, McIver SR, Haydon PG (2011) Gliotransmission modulates baseline mechanical nociception. Mol Pain 7:93. doi:10.1186/1744-8069-7-93
287. Zhuang ZY, Wen YR, Zhang DR et al (2006) A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560. doi:10.1523/JNEUROSCI.5290-05.2006
288. Colburn RW, DeLeo JA, Rickman AJ et al (1997) Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 79:163–175
289. Nakagawa T, Wakamatsu K, Zhang N et al (2007) Intrathecal administration of ATP produces long-lasting allodynia in rats: differential mechanisms in the phase of the induction and maintenance. Neuroscience 147:445–455. doi:10.1016/j.neuroscience.2007.03.045
290. Liu W, Tang Y, Feng J (2011) Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 89:141–146. doi:10.1016/j.lfs.2011.05.011
291. Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11. doi:10.1016/j.it.2006.11.007
292. Sofroniew MV, Vinters HV (2009) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. doi:10.1007/s00401-009-0619-8
293. Miyoshi K, Obata K, Kondo T et al (2008) Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 28:12775–12787. doi:10.1523/JNEUROSCI.3512-08.2008
294. Jin S-X, Zhuang Z-Y, Woolf CJ, 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
295. Piao ZG, Cho I-H, Park CK et al (2006) Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain 121:219–231. doi:10.1016/j.pain.2005.12.023
296. Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29:3518–3528. doi:10.1523/JNEUROSCI.5714-08.2009
297. Gomes C, Ferreira R, George J et al (2013) Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia. J Neuroinflamm 10:16. doi:10.1038/nm1103
298. Torsney C, MacDermott AB (2005) Neuroscience: a painful factor. Nature 438:923–925. doi:10.1038/438923a
299. Yang J, Siao C-J, Nagappan G et al (2009) Neuronal release of proBDNF. Nat Neurosci 12:113–115. doi:10.1038/nn.2244
300. Woo NH, Teng HK, Siao CJ et al (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8:1069–1077. doi:10.1038/nn1510
301. Petersen CM, Nielsen MS, Nykjaer A et al (1997) Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem 272:3599–3605
302. Coull JAM, Boudreau D, Bachand K et al (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942. doi:10.1038/nature01868
303. Coull JAM, Beggs S, Boudreau D et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. doi:10.1038/nature04223
304. Bohlhalter S, Weinmann O, Mohler H, Fritschy JM (1996) Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord: an immunohistochemical study. J Neurosci 16:283–297
305. Bormann J, Hamill OP, Sakmann B (1987) Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones. J Physiol 385:243–286
306. Jonas P, Bischofberger J, Sandkühler J (1998) Corelease of two fast neurotransmitters at a central synapse. Science (New York, NY) 281:419–424
307. Keller AF, Coull JAM, Chéry N et al (2001) Region-specific developmental specialization of GABA–glycine cosynapses in laminas I–II of the rat spinal dorsal horn. J Neurosci 21:7871–7880
308. Rivera C, Voipio J, Thomas-Crusells J et al (2004) Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. J Neurosci 24:4683–4691. doi:10.1523/JNEUROSCI.5265-03.2004
309. Nabekura J, Ueno T, Okabe A et al (2002) Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury. J Neurosci 22:4412–4417
310. − cotransporter KCC2 and impairs neuronal Cl- extrusion. J Cell Biol 159:747–752. doi:10.1083/jcb.200209011
311. Zhang X, Wang J, Zhou Q et al (2011) Brain-derived neurotrophic factor-activated astrocytes produce mechanical allodynia in neuropathic pain. Neuroscience 199:452–460. doi:10.1016/j.neuroscience.2011.10.017
312. Constandil L, Goich M, Hernández A et al (2012) Cyclotraxin-B, a new TrkB antagonist, and glial blockade by propentofylline, equally prevent and reverse cold allodynia induced by BDNF or partial infraorbital nerve constriction in mice. J Pain 13:579–589. doi:10.1016/j.jpain.2012.03.008