Role of Nerve Growth Factor in Pain

  • Kazue MizumuraEmail author
  • Shiori Murase
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)


Nerve growth factor (NGF) was first identified as a substance that is essential for the development of nociceptive primary neurons and later found to have a role in inflammatory hyperalgesia in adults. Involvement of NGF in conditions with no apparent inflammatory signs has also been demonstrated. In this review we look at the hyperalgesic effects of exogenously injected NGF into different tissues, both human and animal, with special emphasis on the time course of these effects. The roles of NGF in inflammatory and neuropathic conditions as well as cancer pain are then reviewed. The role of NGF in delayed onset muscle soreness is described in more detail than its other roles based on the authors’ recent observations. Acute effects are considered to be peripherally mediated, and accordingly, sensitization of nociceptors by NGF to heat and mechanical stimulation has been reported. Changes in the conductive properties of axons have also been reported. The intracellular mechanisms so far proposed for heat sensitization are direct phosphorylation and membrane trafficking of TRPV1 by TrkA. Little investigation has been done on the mechanism of mechanical sensitization, and it is still unclear whether mechanisms similar to those for heat sensitization work in mechanical sensitization. Long-lasting sensitizing effects are mediated both by changed expression of neuropeptides and ion channels (Na channels, ASIC, TRPV1) in primary afferents and by spinal NMDA receptors. Therapeutic perspectives are briefly discussed at the end of the chapter.


Neuropathic pain Cancer pain Noninflammatory pain Delayed onset muscle soreness Mechanical hyperalgesia Heat hyperalgesia 


  1. Aloe L, Tuveri MA, Carcassi U, Levi-Montalcini R (1992) Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum 35:351–355PubMedCrossRefGoogle Scholar
  2. Amann R, Schuligoi R, Herzog G, Donnerer J (1996) Intraplantar injection of nerve growth factor into the rat hind paw: local edema and effects on thermal nociceptive threshold. Pain 64:323–329PubMedCrossRefGoogle Scholar
  3. Andersen H, Arendt-Nielsen L, Danneskiold-Samsoe B, Graven-Nielsen T (2006) Pressure pain sensitivity and hardness along human normal and sensitized muscle. Somatosens Mot Res 23:97–109PubMedCrossRefGoogle Scholar
  4. Andersen H, Arendt-Nielsen L, Svensson P, Danneskiold-Samsoe B, Graven-Nielsen T (2008) Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans. Exp Brain Res 191:371–382PubMedCrossRefGoogle Scholar
  5. Andreev NY, Dimitrieva N, Koltzenburg M, Mcmahon SB (1995) Peripheral administration of nerve growth factor in the adult rat produces a thermal hyperalgesia that requires the presence of sympathetic post-ganglionic neurones. Pain 63:109–115PubMedCrossRefGoogle Scholar
  6. Armstrong RB (1984) Mechanisms of exercise-induced delayed onset muscular soreness: a brief review. Med Sci Sports Exerc 16:529–538PubMedGoogle Scholar
  7. Bennett DLH, Koltzenburg M, Priestley JV, Shelton DL, Mcmahon SB (1998) Endogenous nerve growth factor regulates the sensitivity of nociceptors in the adult rat. Eur J Neurosci 10:1282–1291PubMedCrossRefGoogle Scholar
  8. 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 255:87–90PubMedCrossRefGoogle Scholar
  9. Berry A, Bindocci E, Alleva E (2012) NGF, brain and behavioral plasticity. Neural Plast 2012:784040PubMedCentralPubMedGoogle Scholar
  10. Bhave G, Hu HJ, Glauner KS, Zhu W, Wang H, Brasier DJ, Oxford GS, Gereau RW (2003) Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci U S A 100:12480–12485PubMedCentralPubMedCrossRefGoogle Scholar
  11. Bhide AA, Cartwright R, Khullar V, Digesu GA (2013) Biomarkers in overactive bladder. Int Urogynecol J 24:1065–1072PubMedCrossRefGoogle Scholar
  12. Bielefeldt K, Ozaki N, Gebhart GF (2003) Role of nerve growth factor in modulation of gastric afferent neurons in the rat. Am J Physiol Gastrointest Liver Physiol 284:G499–G507PubMedCrossRefGoogle Scholar
  13. Bloom AP, Jimenez-Andrade JM, Taylor RN, Castaneda-Corral G, Kaczmarska MJ, Freeman KT, Coughlin KA, Ghilardi JR, Kuskowski MA, Mantyh PW (2011) Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers. J Pain 12:698–711PubMedCentralPubMedCrossRefGoogle Scholar
  14. Boix F, Rosenborg L, Hilgenfeldt U, Knardahl S (2002) Contraction-related factors affect the concentration of a kallidin-like peptide in rat muscle tissue. J Physiol 544:127–136PubMedCentralPubMedCrossRefGoogle Scholar
  15. Bonnington JK, McNaughton PA (2003) Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol 551:433–446PubMedCentralPubMedCrossRefGoogle Scholar
  16. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824PubMedCrossRefGoogle Scholar
  17. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Kolzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313PubMedCrossRefGoogle Scholar
  18. Chen TC, Nosaka K, Sacco P (2007) Intensity of eccentric exercise, shift of optimum angle, and the magnitude of repeated-bout effect. J Appl Physiol 102:992–999PubMedCrossRefGoogle Scholar
  19. Cheung K, Hume P, Maxwell L (2003) Delayed onset muscle soreness: treatment strategies and performance factors. Sports Med 33:145–164PubMedCrossRefGoogle Scholar
  20. Chuang H-H, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962PubMedCrossRefGoogle Scholar
  21. Crameri RM, Aagaard P, Qvortrup K, Langberg H, Olesen J, Kjaer M (2007) Myofibre damage in human skeletal muscle: effects of electrical stimulation versus voluntary contraction. J Physiol 583:365–380PubMedCentralPubMedCrossRefGoogle Scholar
  22. Crowley C, Spencer SD, Nishimura MC, Chen KS, Pittsmeek S, Armanini MP, Ling LH, Mcmahon SB, Shelton DL, Levinson AD, Phillips HS (1994) Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001–1011PubMedCrossRefGoogle Scholar
  23. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187PubMedCrossRefGoogle Scholar
  24. De Col R, Messlinger K, Carr RW (2008) Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges. J Physiol 586:1089–1103PubMedCentralPubMedCrossRefGoogle Scholar
  25. Deising S, Weinkauf B, Blunk J, Obreja O, Schmelz M, Rukwied R (2012) NGF-evoked sensitization of muscle fascia nociceptors in humans. Pain 153:1673–1679PubMedCrossRefGoogle Scholar
  26. Di Castro A, Drew LJ, Wood JN, Cesare P (2006) Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways. Proc Natl Acad Sci U S A 103:4699–4704PubMedCentralPubMedCrossRefGoogle Scholar
  27. di Mola FF, Friess H, Zhu ZW, Koliopanos A, Bley T, Di Sebastiano P, Innocenti P, Zimmermann A, Buchler MW (2000) Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease. Gut 46:670–679PubMedCrossRefGoogle Scholar
  28. Djouhri L, Dawbarn D, Robertson A, Newton R, Lawson SN (2001) Time course and nerve growth factor dependence of inflammation-induced alterations in electrophysiological membrane properties in nociceptive primary afferent neurons. J Neurosci 21:8722–8733PubMedGoogle Scholar
  29. Donnerer J, Schuligoi R, Stein C (1992) Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 49:693–698PubMedCrossRefGoogle Scholar
  30. Donnerer J, Schuligoi R, Stein C, Amann R (1993) Upregulation, release and axonal transport of substance-P and calcitonin gene-related peptide in adjuvant inflammation and regulatory function of nerve growth factor. Regul Pept 46:150–154PubMedGoogle Scholar
  31. Donnerer J, Liebmann I, Schicho R (2005) Differential regulation of 3-beta-hydroxysteroid dehydrogenase and vanilloid receptor TRPV1 mRNA in sensory neurons by capsaicin and NGF. Pharmacology 73:97–101PubMedCrossRefGoogle Scholar
  32. Dyck PJ, Peroutka S, Rask C, Burton E, Baker MK, Lehman KA, Gillen DA, Hokanson JL, O’Brien PC (1997) Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 48:501–505PubMedCrossRefGoogle Scholar
  33. Eibl JK, Strasser BC, Ross GM (2012) Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 61:1266–1275PubMedCrossRefGoogle Scholar
  34. Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13:799–805PubMedCrossRefGoogle Scholar
  35. Fjell J, Cummins TR, Dib-Hajj SD, Fried K, Black JA, Waxman SG (1999) Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons. Mol Brain Res 67:267–282PubMedCrossRefGoogle Scholar
  36. Freemont AJ, Watkins A, Le MC, Baird P, Jeziorska M, Knight MT, Ross ER, O’Brien JP, Hoyland JA (2002) Nerve growth factor expression and innervation of the painful intervertebral disc. J Pathol 197:286–292PubMedCrossRefGoogle Scholar
  37. Fujii Y, Ozaki N, Taguchi T, Mizumura K, Sugiura Y (2008) TRP channels and ASICs mediate mechanical hyperalgesia in models of inflammatory muscle pain and delayed onset muscle soreness. Pain 140:292–304PubMedCrossRefGoogle Scholar
  38. Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K (2001) Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci 21:4891–4900PubMedGoogle Scholar
  39. Ghilardi JR, Freeman KT, Jimenez-Andrade JM, Mantyh WG, Bloom AP, Bouhana KS, Trollinger D, Winkler J, Lee P, Andrews SW, Kuskowski MA, Mantyh PW (2011) Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibers. Bone 48:389–398PubMedCentralPubMedCrossRefGoogle Scholar
  40. Giovengo SL, Russell IJ, Larson AA (1999) Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol 26:1564–1569PubMedGoogle Scholar
  41. Guo TZ, Offley SC, Boyd EA, Jacobs CR, Kingery WS (2004) Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I. Pain 108:95–107PubMedCrossRefGoogle Scholar
  42. Halliday DA, Zettler C, Rush RA, Scicchitano R, McNeil JD (1998) Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease. Neurochem Res 23:919–922PubMedCrossRefGoogle Scholar
  43. Halvorson KG, Kubota K, Sevcik MA, Lindsay TH, Sotillo JE, Ghilardi JR, Rosol TJ, Boustany L, Shelton DL, Mantyh PW (2005) A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res 65:9426–9435PubMedCrossRefGoogle Scholar
  44. Hayashi K, Shiozawa S, Ozaki N, Mizumura K, Graven-Nielsen T (2013) Repeated intramuscular injections of nerve growth factor induced progressive muscle hyperalgesia, facilitated temporal summation and expanded pain areas. Pain 154:2344–2352PubMedCrossRefGoogle Scholar
  45. Hirth M, Rukwied R, Gromann A, Turnquist B, Weinkauf B, Francke K, Albrecht P, Rice F, Hagglof B, Ringkamp M, Engelhardt M, Schultz C, Schmelz M, Obreja O (2013) Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain 154:2500–2511PubMedCrossRefGoogle Scholar
  46. Hoheisel U, Unger T, Mense S (2005) Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat. Pain 114:168–176PubMedCrossRefGoogle Scholar
  47. Hoheisel U, Taguchi T, Treede RD, Mense S (2011) Nociceptive input from the rat thoracolumbar fascia to lumbar dorsal horn neurones. Eur J Pain 15:810–815PubMedCrossRefGoogle Scholar
  48. Hoheisel U, Taguchi T, Mense S (2012) Nociception: the thoracolumbar fascia as a sensory organ. In: Schleip R, Findley TW, Chaitow L, Huijing PA (eds) Fascia: the tensional network of the human body: the science and clinical applications in manual and movement therapy. Churchill Livingstone/Elsevier, Edinburgh, pp 95–101Google Scholar
  49. Iannone F, De BC, Dell’Accio F, Covelli M, Patella V, Lo BG, Lapadula G (2002) Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology 41:1413–1418PubMedCrossRefGoogle Scholar
  50. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I (1996) Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13:485–488PubMedCrossRefGoogle Scholar
  51. Itoh K, Okada K, Kawakita K (2004) A proposed experimental model of myofascial trigger points in human muscle after slow eccentric exercise. Acupunct Med 22:2–12PubMedCrossRefGoogle Scholar
  52. Iwakura N, Ohtori S, Orita S, Yamashita M, Takahashi K, Kuniyoshi K (2010) Role of low-affinity nerve growth factor receptor inhibitory antibody in reducing pain behavior and calcitonin gene-related Peptide expression in a rat model of wrist joint inflammatory pain. J Hand Surg Am 35:267–273PubMedCrossRefGoogle Scholar
  53. Ji R, Samad T, Jin S, Schmoll R, Woolf C (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68PubMedCrossRefGoogle Scholar
  54. Jiang YH, Peng CH, Liu HT, Kuo HC (2013) Increased pro-inflammatory cytokines, C-reactive protein and nerve growth factor expressions in serum of patients with interstitial cystitis/bladder pain syndrome. PLoS One 8:e76779PubMedCentralPubMedCrossRefGoogle Scholar
  55. Kawakita K, Itoh K, Okada K (2008) Experimental model of trigger points using eccentric exercise. J Musculoskelet Pain 16:29–35CrossRefGoogle Scholar
  56. Khodorova A, Nicol GD, Strichartz G (2013) The p75(NTR) signaling cascade mediates mechanical hyperalgesia induced by nerve growth factor injected into the rat hind paw. Neuroscience 254:312–323PubMedCrossRefGoogle Scholar
  57. Kim JC, Park EY, Seo SI, Park YH, Hwang TK (2006) Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol 175:1773–1776PubMedCrossRefGoogle Scholar
  58. Kivitz AJ, Gimbel JS, Bramson C, Nemeth MA, Keller DS, Brown MT, West CR, Verburg KM (2013) Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. Pain 154:1009–1021PubMedCrossRefGoogle Scholar
  59. Koltzenburg M, Bennett DL, Shelton DL, Mcmahon SB (1999) Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin. Eur J Neurosci 11:1698–1704PubMedCrossRefGoogle Scholar
  60. Lamb K, Gebhart GF, Bielefeldt K (2004) Increased nerve growth factor expression triggers bladder overactivity. J Pain 5:150–156PubMedCrossRefGoogle Scholar
  61. Leslie TA, Emson PC, Dowd PM, Woolf CJ (1995) Nerve growth factor contributes to the up-regulation of growth- associated protein 43 and preprotachykinin A messenger RNAs in primary sensory neurons following peripheral inflammation. Neuroscience 67:753–761PubMedCrossRefGoogle Scholar
  62. Lewin GR, Nykjaer A (2014) Pro-neurotrophins, sortilin, and nociception. Eur J Neurosci 39:363–374PubMedCentralPubMedCrossRefGoogle Scholar
  63. Lewin GR, Winter J, Mcmahon SB (1992) Regulation of afferent connectivity in the adult spinal cord by nerve growth factor. Eur J Neurosci 4:700–707PubMedCrossRefGoogle Scholar
  64. Lewin GR, Ritter AM, Mendell LM (1993) Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci 13:2136–2148PubMedGoogle Scholar
  65. Lewin GR, Rueff A, Mendell LM (1994) Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur J Neurosci 6:1903–1912PubMedCrossRefGoogle Scholar
  66. Liu HT, Chancellor MB, Kuo HC (2009) Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int 103:1668–1672PubMedCrossRefGoogle Scholar
  67. Liu HT, Jiang YH, Kuo HC (2013) Increased serum adipokines implicate chronic inflammation in the pathogenesis of overactive bladder syndrome refractory to antimuscarinic therapy. PLoS One 8:e76706PubMedCentralPubMedCrossRefGoogle Scholar
  68. Malik-Hall M, Dina OA, Levine JD (2005) Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia. Eur J Neurosci 21:3387–3394PubMedCrossRefGoogle Scholar
  69. Mamet J, Baron A, Lazdunski M, Voilley N (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci 22:10662–10670PubMedGoogle Scholar
  70. Mann MK, Dong XD, Svensson P, Cairns BE (2006) Influence of intramuscular nerve growth factor injection on the response properties of rat masseter muscle afferent fibers. J Orofac Pain 20:325–336PubMedGoogle Scholar
  71. Matsuura Y, Iwakura N, Ohtori S, Suzuki T, Kuniyoshi K, Murakami K, Hiwatari R, Hashimoto K, Okamoto S, Shibayama M, Kobayashi T, Ogawa Y, Sukegawa K, Takahashi K (2013) The effect of Anti-NGF receptor (p75 Neurotrophin Receptor) antibodies on nociceptive behavior and activation of spinal microglia in the rat brachial plexus avulsion model. Spine (Phila Pa 1976) 38:E332–E338CrossRefGoogle Scholar
  72. Mcmahon SB, Bennett DL, Priestley JV, Shelton DL (1995) The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule. Nat Med 1:774–780PubMedCrossRefGoogle Scholar
  73. McNamee KE, Burleigh A, Gompels LL, Feldmann M, Allen SJ, Williams RO, Dawbarn D, Vincent TL, Inglis JJ (2010) Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain 149:386–392PubMedCrossRefGoogle Scholar
  74. Murase S, Terazawa E, Queme F, Ota H, Matsuda T, Hirate K, Kozaki Y, Katanosaka K, Taguchi T, Mizumura K (2010) Bradykinin and nerve growth factor play pivotal roles in muscular mechanical hyperalgesia after exercise (delayed onset muscle soreness). J Neurosci 30:3752–3761PubMedCrossRefGoogle Scholar
  75. Murase S, Yamanaka Y, Kanda H, Mizumura K (2012) COX-2, nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF), which play pivotal roles in delayed onset muscle soreness (DOMS), are produced by exercised skeletal muscle. J Physiol Sci 62(Suppl):S179Google Scholar
  76. Murase S, Terazawa E, Hirate K, Yamanaka H, Kanda H, Noguchi K, Ota H, Queme F, Taguchi T, Mizumura K (2013) Upregulated glial cell line-derived neurotrophic factor through cyclooxygenase-2 activation in the muscle is required for mechanical hyperalgesia after exercise in rats. J Physiol 591:3035–3048PubMedCentralPubMedCrossRefGoogle Scholar
  77. Nicol GD, Vasko MR (2007) Unraveling the story of NGF-mediated sensitization of nociceptive sensory neurons: ON or OFF the Trks? Mol Interv 7:26–41PubMedCrossRefGoogle Scholar
  78. Nishigami T, Osako Y, Ikeuchi M, Yuri K, Ushida T (2013) Development of heat hyperalgesia and changes of TRPV1 and NGF expression in rat dorsal root ganglion following joint immobilization. Physiol Res 62:215–219PubMedGoogle Scholar
  79. Oddiah D, Anand P, Mcmahon SB, Rattray M (1998) Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport 9:1455–1458PubMedCrossRefGoogle Scholar
  80. Ohmichi Y, Sato J, Ohmichi M, Sakurai H, Yoshimoto T, Morimoto A, Hashimoto T, Eguchi K, Nishihara M, Arai YC, Ohishi H, Asamoto K, Ushida T, Nakano T, Kumazawa T (2012) Two-week cast immobilization induced chronic widespread hyperalgesia in rats. Eur J Pain 16:338–348PubMedCrossRefGoogle Scholar
  81. Ota H, Katanosaka K, Murase S, Kashio M, Tominaga M, Mizumura K (2013) TRPV1 and TRPV4 play pivotal roles in delayed onset muscle soreness. PLoS One 8:e65751PubMedCentralPubMedCrossRefGoogle Scholar
  82. Pantano F, Zoccoli A, Iuliani M, Lanzetta G, Vincenzi B, Tonini G, Santini D (2011) New targets, new drugs for metastatic bone pain: a new philosophy. Expert Opin Emerg Drugs 16:403–405PubMedCrossRefGoogle Scholar
  83. Petty BG, Cornblath DR, Adornato BT, Chaudhry V, Flexner C, Wachsman M, Sinicropi D, Burton LE, Peroutka SJ (1994) The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 36:244–246PubMedCrossRefGoogle Scholar
  84. Queme F, Taguchi T, Mizumura K, Graven-Nielsen T (2013) Muscular heat and mechanical pain sensitivity after lengthening contractions in humans and animals. J Pain 14:1425–1436PubMedCrossRefGoogle Scholar
  85. Ritter AM, Lewin GR, Kremer NE, Mendell LM (1991) Requirement for nerve growth factor in the development of myelinated nociceptors in vivo. Nature 350:500–502PubMedCrossRefGoogle Scholar
  86. Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M (2010) NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 148:407–413PubMedCrossRefGoogle Scholar
  87. Sanga P, Katz N, Polverejan E, Wang S, Kelly KM, Haeussler J, Thipphawong J (2013) Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. Pain 154:1910–1919PubMedCrossRefGoogle Scholar
  88. Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K, Acciarresi M, Pini LA, Calabresi P (2007) Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain 8:737–745PubMedCrossRefGoogle Scholar
  89. Schmieg N, Menendez G, Schiavo G, Terenzio M (2014) Signalling endosomes in axonal transport: travel updates on the molecular highway. Semin Cell Dev Biol 27:32–43. doi: 10.1016/j.semcdb.2013.10.004 PubMedCrossRefGoogle Scholar
  90. Sekino Y, Nakano J, Hamaue Y, Chuganji S, Sakamoto J, Yoshimura T, Origuchi T, Okita M (2014) Sensory hyperinnervation and increase in NGF, TRPV1 and P2X3 expression in the epidermis following cast immobilization in rats. Eur J Pain 18:639–648PubMedCrossRefGoogle Scholar
  91. Shu X, Mendell LM (1999) Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett 274:159–162PubMedCrossRefGoogle Scholar
  92. Shu X, Mendell LM (2001) Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin. J Neurophysiol 86:2931–2938PubMedGoogle Scholar
  93. Smith LL (1991) Acute inflammation—the underlying mechanism in delayed onset muscle soreness. Med Sci Sports Exerc 23:542–551PubMedGoogle Scholar
  94. Stein AT, Ufret-Vincenty CA, Hua L, Santana LF, Gordon SE (2006) Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J Gen Physiol 128:509–522PubMedCentralPubMedCrossRefGoogle Scholar
  95. Svensson P, Cairns BE, Wang K, Arendt-Nielsen L (2003) Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain 104:241–247PubMedCrossRefGoogle Scholar
  96. Taguchi T, Matsuda T, Tamura R, Sato J, Mizumura K (2005a) Muscular mechanical hyperalgesia revealed by behavioural pain test and c-Fos expression in the spinal dorsal horn after eccentric contraction in rats. J Physiol 564:259–268PubMedCentralPubMedCrossRefGoogle Scholar
  97. Taguchi T, Sato J, Mizumura K (2005b) Augmented mechanical response of muscle thin-fiber sensory receptors recorded from rat muscle-nerve preparations in vitro after eccentric contraction. J Neurophysiol 94:2822–2831PubMedCrossRefGoogle Scholar
  98. Taguchi T, Hoheisel U, Mense S (2008a) Dorsal horn neurons having input from low back structures in rats. Pain 138:119–129PubMedCrossRefGoogle Scholar
  99. Taguchi T, Hoheisel U, Mense S (2008b) Neuroanatomy and electrophysiology of low back pain: experiments on rats. Aktuelle Urol 34:472–477CrossRefGoogle Scholar
  100. Taguchi T, Yasui M, Kubo A, Abe M, Kiyama H, Yamanaka A, Mizumura K (2013) Nociception originating from the crural fascia in rats. Pain 154:1103–1114PubMedCrossRefGoogle Scholar
  101. Urai H, Murase S, Mizumura K (2012) Decreased nerve growth factor upregulation is a mechanism for reduced mechanical hyperalgesia after the second bout of exercise in rats. Scand J Med Sci Sports 23:e96–e101PubMedCrossRefGoogle Scholar
  102. Wild KD, Bian D, Zhu D, Davis J, Bannon AW, Zhang TJ, Louis JC (2007) Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Ther 322:282–287PubMedCrossRefGoogle Scholar
  103. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J (1994) Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62:327–331PubMedCrossRefGoogle Scholar
  104. Woolf CJ, Ma QP, Allchorne A, Poole S (1996) Peripheral cell types contributing to the hyperalgesic action of nerve growth factor in inflammation. J Neurosci 16:2716–2723PubMedGoogle Scholar
  105. Xue Q, Jong B, Chen T, Schumacher MA (2007) Transcription of rat TRPV1 utilizes a dual promoter system that is positively regulated by nerve growth factor. J Neurochem 101:212–222PubMedCrossRefGoogle Scholar
  106. Ye Y, Dang D, Zhang J, Viet CT, Lam DK, Dolan JC, Gibbs JL, Schmidt BL (2011) Nerve growth factor links oral cancer progression, pain, and cachexia. Mol Cancer Ther 10:1667–1676PubMedCentralPubMedCrossRefGoogle Scholar
  107. Zhang X, Huang J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24:4211–4223PubMedCentralPubMedCrossRefGoogle Scholar
  108. Zhang YH, Kays J, Hodgdon KE, Sacktor TC, Nicol GD (2012) Nerve growth factor enhances the excitability of rat sensory neurons through activation of the atypical protein kinase C isoform, PKMzeta. J Neurophysiol 107:315–335PubMedCentralPubMedCrossRefGoogle Scholar
  109. Zhu W, Oxford GS (2007) Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1. Mol Cell Neurosci 34:689–700PubMedCentralPubMedCrossRefGoogle Scholar
  110. Zhu W, Galoyan SM, Petruska JC, Oxford GS, Mendell LM (2004) A developmental switch in acute sensitization of small dorsal root ganglion (DRG) neurons to capsaicin or noxious heating by NGF. J Neurophysiol 92:3148–3152PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Physical TherapyCollege of Life and Health Sciences, Chubu UniversityKasugaiJapan

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