Activation of neurotrophins in lumbar dorsal root probably contributes to neuropathic pain after spinal nerve ligation

Document Type: Original Article

Authors

1 Department of Physical Education and Sports Sciences, Faculty of Humanity and Literature, Vali E Asr University of Rafsanjan, Rafsanjan, Iran

2 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Departments of Physical Education and Sports Sciences, Lorestan University, Khoram Abad, Iran

4 Department of corrective exercise and Sports injury, Faculty of Physical Education and Sports Sciences, Allameh Tabataba’i University, Tehran, Iran

Abstract

Objective(s): Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root.
Materials and Methods: Ten male Wistar rats were ran‌domly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5). In order to produce neuropathic pain, the L5 spinal nerve was tightly ligated (SNL). Then, allodynia and hyperalgesia tests were conducted weekly. After 4 weeks, tissue samples were taken from the two groups for laboratory evaluations. Here, Real-Time PCR quantity method was used for measuring NTs gene expression levels.
Results: SNL resulted in a significant weight loss in the soleus muscle (P<0.05), mechanical allodynia and thermal hyperalgesia thresholds (respectively, P<0.05; P<0.05). Also, NGF, NT-4, NT-3, TrkA, TrkB and TrkC expression were up-regulated following spinal nerve ligation group (respectively, P=0.025, P=0.013, P=0.001, P=0.002, P<0.001, P=001) (respectively, 4.7, 5.2, 7.5, 5.1, 7.2, 6.2 folds).
Conclusion: The present study provides new evidence that neuropathic pain induced by spinal nerve ligation probably activates NTs and Trk receptors expression in DRG. However, further studies are needed to better elucidate the role of NTs in a neuropathic pain.

Keywords


1. Ashton JC. Neuropathic pain: An evolutionary hypothesis. Med Hypotheses 2012; 78:641–643.

2. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology 2008; 70:1630–1635.

3. Siniscalco D, Giordano C, Rossi F, Maione S, Novellis VD. Role of neurotrophins in neuropathic pain. Curr Neuropharmacol 2011; 9:523-529.

4. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg E. CREB: a major mediator of neuronal neurotrophin responses. Neuron 1997; 19:1031-1047.

5. Levi-Montalcini R. Tissue and nerve growth promoting factors. Biological aspects of specific growth promoting factors. Proc R Soc Med 1965; 58:357-360.

6. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 2001; 11:272–280.

7. Klein R, Jing, SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 1991; 65:189-197.

8. Ceni C, Unsain N, Zeinieh MP, Barker PA. Neurotrophins in the regulation of cellular survival and death. Handb. Exp Pharmacol 2014; 220:193–221.

9. Skaper SD. The neurotrophin family of neurotrophic factors: An overview. Methods Mol Biol 2012; 846:1–12.

10. Davies AM. Neurotrophins giveth and they taketh away. Nat Neurosci 2008; 11:627–628.

11. Khan N, Smith MT. Neurotrophins and neuropathic pain: role in pathobiology. Molecules 2015; 20:10657-10688.

12. Nijs J, Meeus M, Versijpt J, Moens M, Bos I, Knaepen K, et al. Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: A new therapeutic target? Expert Opin Ther Targets 2015; 19:565–576.

13. McMahon SB, Jones NG. Plasticity of pain signaling: Role of neurotrophic factors exemplified by acid-induced pain. J Neurobiol 2004; 61:72–87.

14. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 2006; 29:507–538.

15.  Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50:355-363.

16. Cruccu G, Anand P, Attal N, Garcia-Larrea L, Haanpää M, Jørum E, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004; 11:153-162.

17. Yin FC, Spurgeon HA, Rakusan K, Weisfeldt ML, Lakatta EG. Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am J Physiol 1982; 243:H941-947.

18. Pfaffl MW. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Res 2001; 29:e45-e45.

19. Vogelaar CF, Vrinten DH, Hoekman MF M, Brakkee JH, Burbach JP, Hamers FPT. Sciatic nerve regeneration in mice and rats: recovery of sensory innervation is followed by a slowly retreating neuropathic pain-like syndrome. Brain Res 2004; 1027:67–72.

20. Ugolini G, Marinelli S, Covaceuszach S, Cattaneo A, Pavone F. The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain. Proc Natl Acad Sci USA 2007; 104:2985–2990.

21. Owolabi JB, Rizkalla G, Tehim A, Ross GM, Riopelle RJ, Kamboj R, et al. Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat. J Pharmacol Exp Ther 1999; 289:1271–1276.

22.  Ro LS, Chen ST, Tang LM, Jacobs JM. Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve. Pain 1999; 79:265–274.

23. Wild KD, Bian D, Zhu D, Davis J, Bannon AW, Zhang TJ, et al. Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance. J Pharmacol Exp Ther 2007; 322:282–287.

24. Lewin GR, Ritter AM, Mendell LM. Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci 1993; 13:2136–2148.

25. Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M. NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 2010; 148:407–413.

26. Thompson SW, Dray A, McCarson KE, Krause JE, Urban L. Nerve growth factor induces mechanical allodynia associated with novel a fibre-evoked spinal reflex activity and enhanced neurokinin-1 receptor activation in the rat. Pain 1995; 62:219–231.

27. Lewin GR, Lechner SG, Smith EJ. Nerve growth factor and nociception: from experimental embryology to new analgesic therapy. Handb Exp Pharmacol 2014; 220:251-282.

28. Lewin GR, Mendell LM. Regulation of cutaneous C-fiber heat nociceptors by nerve growth factor in the developing rat. J Neurophysiol 1994; 71:941–949.

29.  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 2008; 36:57–68.

30.  Shu X, Mendell LM. Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett 1999; 274:159–162.

31. Bonnington JK, McNaughton PA. Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol 2003; 551:433–446.

32. Pezet S, Malcangio M, McMahon SB. BDNF: A neuromodulator in nociceptive pathways? Brain Res Rev 2002; 40:240–249.

33. Zhuang ZY, Gerner P, Woolf CJ, Ji RR. Erk is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114:149–159.

34. Aloe L, Rocco M, Bianchi P, Manni L. Nerve growth factor: From the early discoveries to the potential clinical use. J Transl Med 2012; 10:239.

35. Otten U, Schwab M, Gagnon C, Thoenen H. Selective induction of tyrosine hydroxylase and dopamine beta-hydroxylase by nerve growth factor: Comparison between adrenal medulla and sympathetic ganglia of adult and newborn rats. Brain Res 1977; 133:291–303.

36. Shadiack AM, Sun Y, Zigmond RE. Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurosci 2001; 21:363–371.

37. Wilson-Gerwing TD, Dmyterko MV, Zochodne DW, Johnston JM, Verge VM. Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons. J Neurosci 2005; 25:758–767.

38. Ivanisevic L, Zheng W, Woo SB, Neet KE, Saragovi HU. TrkA receptor “hot spots” for binding of NT-3 as a heterologous ligand. J Biol Chem 2007; 282:16754–16763.

39. Gratto KA, Verge VM. Neurotrophin-3 down-regulates TrkA mRNA, NGF high-affinity binding sites, and associated phenotype in adult DRG neurons. Eur J Neurosci 2003; 18:1535–1548.

40. Wang TH, Meng QS, Qi JG, Zhang WM, Chen J, Wu LF. NT-3 expression in spared DRG and the associated spinal laminae as well as its anterograde transport in sensory neurons following removal of adjacent DRG in cats. Neurochem Res 2008; 33:1–7.

41. Jongsma WH, Danielsen N, Johnston JM, Gratto KA, Karchewski LA, Verge VM. Exogenous NT-3 and NGF differentially modulate PACAP expression in adult sensory neurons, suggesting distinct roles in injury and inflammation. Eur J Neurosci 2001; 14:267–282.

42. Karchewski LA, Gratto KA, Wetmore C, Verge VM. Dynamic patterns of BDNF expression in injured sensory neurons: differential modulation byNGFand NT-3. Eur J Neurosci 2002; 16:1449 –1462.

43. Verge VM, Riopelle RJ, Richardson PM. Nerve growth factor receptors on normal and injured sensory neurons. J Neurosci 1990; 9:914 –922.

44. Verge VM, Richardson PM, Benoit R, Riopelle RJ. Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor. J Neurocytol 1989; 18:583–591.

45. Verge VM, Zhang X, Xu XJ, Wiesenfeld-Hallin Z,  Hokfelt T. Marked increase in nitric oxide synthase mRNA in rat dorsal root ganglia after peripheral
axotomy: in situ hybridization and functional studies. Proc Natl Acad Sci USA 1992; 89:11617–11621.

46. Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hokfelt T. Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci 1995; 15:2081–2096.

47. Yajima Y, Narita M, Narita M, Matsumoto N, Suzuki T. 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 2002; 958:338–346.

48. Hibbert AP, Morris SJ, Seidah NG, Murphy RA. Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway. J Biol Chem 2003; 278:48129–48136.

49. Buck CR, Seburn KL, Cope TC. Neurotrophin expression by spinal motoneurons in adult and developing rats. J Comp Neurol 2000; 416:309–318.

50. Heppenstall PA, Lewin GR. BDNF but not NT-4 is required for normal flexion reflex plasticity and function. Proc Natl Acad Sci USA 2001; 98:8107–8112.

51. Rodriguez-Pena A, Botana M, Gonzalez M, Requejo F. Expression of neurotrophins and their receptors in sciatic nerve of experimentally diabetic rats. Neurosci Lett 1995: 200:37–40.

52. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci USA 2005; 102:19045–19050.

53. Yin Q, Kemp GJ, Yu LG, Wagstaff SC, Frostick SP. Expression of Schwann cell-specific proteins and low-molecularweight neurofilament protein during regeneration of sciatic nerve treated with neurotrophin-4. Neuroscience 2001; 105:779-783.

54. Geng SJ, Liao FF, Dang WH, Ding X, Liu XD, Cai J, et al. Contribution of the spinal cord BDNF to the development of neuropathic pain by activation of the NR2B-containing NMDA receptors in rats with spinal nerve ligation. Exp Neurol 2010; 222:256-266.

55. Li L, Xian CJ, Zhong JH, Zhou XF. Upregulation of brainderived neurotrophic factor in the sensory pathway by selective motor nerve injury in adult rats. Neurotox Res 2006; 9:269-283.