Expression of TRPV1 channels after nerve injury provides an essential delivery tool for neuropathic pain attenuation.

Zakir, HM and Mostafeezur, RM and Suzuki, A and Hitomi, S and Maeda, T and Seo, K and Yamada, Y and Yamamura, K and Lev, S and Binshtok, AM and Iwata, K and Kitagawa, J (2012): Expression of TRPV1 channels after nerve injury provides an essential delivery tool for neuropathic pain attenuation. Published in: Plos One , Vol. 7, No. 9 (4 September 2012)

Abstract

Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP) - induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions.

• Item Type: MPRA Paper
• Language: English
• Keywords: Dorsal-root ganglion; Inferior alveolar nerve; Complete Freunds-adjuvant; Afferent sensory neurons; Gene-expression; Schawann-cells; Vanilloid receptor-1; Local anesthetics; Sciatic-nerve; Differential changes
• Subjects: I - Health, Education, and Welfare > I0 - General > I00 - General

References

1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, et al. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816–824.

2. Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, et al. (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129: 227–230.

3. Tominaga M, Caterina MJ (2004) Thermosensation and pain. J Neurobiol 61: 3–12.

4. Tominaga M, Tominaga T (2005) Structure and function of TRPV1. Pflugers Arch 451: 143–150.

5. Biggs JE, Yates JM, Loescher AR, Clayton NM, Boissonade FM, et al. (2007) Changes in vanilloid receptor 1 (TRPV1) expression following lingual nerve injury. Eur J Pain 11: 192–201.

6. Fukuoka T, Tokunaga A, Tachibana T, Dai Y, Yamanaka H, et al. (2002) VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain 99: 111–120.

7. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, et al. (2001) VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 13: 2105–2114.

8. Kanai Y, Nakazato E, Fujiuchi A, Hara T, Imai A (2005) Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats. Neuropharmacology 49: 977–984.

9. Kim HY, Park CK, Cho IH, Jung SJ, Kim JS, et al. (2008) Differential Changes in TRPV1 expression after trigeminal sensory nerve injury. J Pain 9: 280–288.

10. Michael GJ, Priestley JV (1999) Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. J Neurosci 19: 1844–1854.

11. Bianchi CP, Bolton TC (1967) Action of local anesthetics on coupling systems in muscle. J Pharmacol Exp Ther 157: 388–405.

12. O'Brien RD (1967) Barrier systems in insect ganglia and their implications for toxicology. Fed Proc 26: 1056–1061. 13. Ritchie JM, Ritchie B, Greengard P (1965) The active structure of local anesthetics. J Pharmacol Exp Ther 150: 152–159.

14. Ritchie JM, Ritchie B, Greengard P (1965) The effect of the nerve sheath on the action of local anesthetics. J Pharmacol Exp Ther 150: 160–164.

15. Binshtok AM (2011) Mechanisms of nociceptive transduction and transmission: a machinery for pain sensation and tools for selective analgesia. Int Rev Neurobiol 97: 143–177.

16. Binshtok AM, Bean BP, Woolf CJ (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449: 607–610.

17. Kim HY, Kim K, Li HY, Chung G, Park CK, et al. (2010) Selectively targeting pain in the trigeminal system. Pain 150: 29–40.

18. Liu H, Zhang HX, Hou HY, Lu XF, Wei JQ, et al. (2011) Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce sensory-specific analgesic effects. PLoS One 6: e29395.

19. Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16: 109–110.

20. Nakagawa K, Takeda M, Tsuboi Y, Kondo M, Kitagawa J, et al. (2011) Alteration of primary afferent activity following inferior alveolar nerve transection in rats. Mol Pain 6: 9.

21. Saito K, Hitomi S, Suzuki I, Masuda Y, Kitagawa J, et al. (2008) Modulation of trigeminal spinal subnucleus caudalis neuronal activity following regeneration of transected inferior alveolar nerve in rats. J Neurophysiol 99: 2251–2263.

22. Kitagawa J, Takeda M, Suzuki I, Kadoi J, Tsuboi Y, et al. (2006) Mechanisms involved in modulation of trigeminal primary afferent activity in rats with peripheral mononeuropathy. Eur J Neurosci 24: 1976–1986.

23. Carter DA, Lisney SJ (1987) The numbers of unmyelinated and myelinated axons in normal and regenerated rat saphenous nerves. J Neurol Sci 80: 163–171.

24. Jabbar S, Harada F, Aita M, Ohishi M, Saito I, et al. (2007) Involvement of neurotrophin-4/5 in regeneration of the periodontal Ruffini endings at the early stage. J Comp Neurol 501: 400–412.

25. Lisney SJ (1987) Functional aspects of the regeneration of unmyelinated axons in the rat saphenous nerve. J Neurol Sci 80: 289–298.

26. Youn SH, Sakuda M, Kurisu K, Wakisaka S (1997) Regeneration of periodontal primary afferents of the rat incisor following injury of the inferior alveolar nerve with special reference to neuropeptide Y-like immunoreactive primary afferents. Brain Res 752: 161–169.

27. Campbell JN (2001) Nerve lesions and the generation of pain. Muscle Nerve 24: 1261–1273.

28. Koerber HR, Mirnics K, Brown PB, Mendell LM (1994) Central sprouting and functional plasticity of regenerated primary afferents. J Neurosci 14: 3655–3671.

29. Koerber HR, Mirnics K, Kavookjian AM, Light AR (1999) Ultrastructural analysis of ectopic synaptic boutons arising from peripherally regenerated primary afferent fibers. J Neurophysiol 81: 1636–1644.

30. Kury P, Stoll G, Muller HW (2001) Molecular mechanisms of cellular interactions in peripheral nerve regeneration. Curr Opin Neurol 14: 635–639.

31. Oaklander AL, Brown JM (2004) Unilateral nerve injury produces bilateral loss of distal innervation. Ann Neurol 55: 639–644.

32. Obata K, Noguchi K (2004) MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 74: 2643–2653.

33. Ruocco I, Cuello AC, Ribeiro-Da-Silva A (2000) Peripheral nerve injury leads to the establishment of a novel pattern of sympathetic fibre innervation in the rat skin. J Comp Neurol 422: 287–296.

34. 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.

35. Terenghi G (1995) Peripheral nerve injury and regeneration. Histol Histopathol 10: 709–718.

36. Bisby MA, Keen P (1986) Regeneration of primary afferent neurons containing substance P-like immunoreactivity. Brain Res 365: 85–95.

37. Decosterd I, Ji RR, Abdi S, Tate S, Woolf CJ (2002) The pattern of expression of the voltage-gated sodium channels Na(v)1.8 and Na(v)1.9 does not change in uninjured primary sensory neurons in experimental neuropathic pain models. Pain 96: 269–277.

38. Ishikawa K, Tanaka M, Black JA, Waxman SG (1999) Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy. Muscle Nerve 22: 502–507.

39. Iwata K, Imai T, Tsuboi Y, Tashiro A, Ogawa A, et al. (2001) Alteration of medullary dorsal horn neuronal activity following inferior alveolar nerve transection in rats. J Neurophysiol 86: 2868–2877.

40. Kim DS, Yoon CH, Lee SJ, Park SY, Yoo HJ, et al. (2001) Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. Brain Res Mol Brain Res 96: 151–156.

41. Kitagawa J, Kanda K, Sugiura M, Tsuboi Y, Ogawa A, et al. (2005) Effect of chronic inflammation on dorsal horn nociceptive neurons in aged rats. J Neurophysiol 93: 3594–3604.

42. Nomura H, Ogawa A, Tashiro A, Morimoto T, Hu JW, et al. (2002) Induction of Fos protein-like immunoreactivity in the trigeminal spinal nucleus caudalis and upper cervical cord following noxious and non-noxious mechanical stimulation of the whisker pad of the rat with an inferior alveolar nerve transection. Pain 95: 225–238.

43. Obata K, Yamanaka H, Fukuoka T, Yi D, Tokunaga A, et al. (2003) Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. Pain 101: 65–77.

44. Smith DS, Skene JH (1997) A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J Neurosci 17: 646–658.

45. Takeda M, Tsuboi Y, Kitagawa J, Nakagawa K, Iwata K, et al. (2011) Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain. Mol Pain 7: 5

46. Tsuboi Y, Takeda M, Tanimoto T, Ikeda M, Matsumoto S, et al. (2004) Alteration of the second branch of the trigeminal nerve activity following inferior alveolar nerve transection in rats. Pain 111: 323–334.

47. Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, et al. (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A 99: 8360–8365

48. Xie W, Matsumoto M, Chun J, Ueda H (2008) Involvement of LPA1 receptor signaling in the reorganization of spinal input through Abeta-fibers in mice with partial sciatic nerve injury. Mol Pain 4: 46

49. Campana WM, Li X, Dragojlovic N, Janes J, Gaultier A, et al. (2006) The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury. J Neurosci 26: 11197–11207.

50. Bhatheja K, Field J (2006) Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol 38: 1995–1999.

51. Lozeron P, Krarup C, Schmalbruch H (2004) Regeneration of unmyelinated and myelinated sensory nerve fibres studied by a retrograde tracer method. J Neurosci Methods 138: 225–232.

52. Vilceanu D, Honore P, Hogan QH, Stucky CL (2010) Spinal nerve ligation in mouse upregulates TRPV1 heat function in injured IB4-positive nociceptors. J Pain 11: 588–599 53. Price DD, Dubner R, Hu JW (1976) Trigeminothalamic neurons in nucleus caudalis responsive to tactile, thermal, and nociceptive stimulation of monkey's face. J Neurophysiol 39: 936–953.

54. Robinson PP, Boissonade FM, Loescher AR, Smith KG, Yates JM, et al. (2004) Peripheral mechanisms for the initiation of pain following trigeminal nerve injury. J Orofac Pain 18: 287–292.

55. Luo H, Cheng J, Han JS, Wan Y (2004) Change of vanilloid receptor 1 expression in dorsal root ganglion and spinal dorsal horn during inflammatory nociception induced by complete Freund's adjuvant in rats. Neuroreport 15: 655–658.

56. Yu L, Yang F, Luo H, Liu FY, Han JS, et al. (2008) The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund's adjuvant. Mol Pain 4: 61

57. Amaya F, Oh-hashi K, Naruse Y, Iijima N, Ueda M, et al. (2003) Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons. Brain Res 963: 190–196.

58. Hong S, Wiley JW (2005) Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 280: 618–627.

59. Niiyama Y, Kawamata T, Yamamoto J, Omote K, Namiki A (2007) Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons. Neuroscience 148: 560–572.

60. Matsumoto M, Xie W, Ma L, Ueda H (2008) Pharmacological switch in Abeta-fiber stimulation-induced spinal transmission in mice with partial sciatic nerve injury. Mol Pain 4: 25

61. Miki K, Fukuoka T, Tokunaga A, Noguchi K (1998) Calcitonin gene-related peptide increase in the rat spinal dorsal horn and dorsal column nucleus following peripheral nerve injury: up-regulation in a subpopulation of primary afferent sensory neurons. Neuroscience 82: 1243–1252.

62. Noguchi K, Dubner R, De Leon M, Senba E, Ruda MA (1994) Axotomy induces preprotachykinin gene expression in a subpopulation of dorsal root ganglion neurons. J Neurosci Res 37: 596–603.

63. Noguchi K, Kawai Y, Fukuoka T, Senba E, Miki K (1995) Substance P induced by peripheral nerve injury in primary afferent sensory neurons and its effect on dorsal column nucleus neurons. J Neurosci 15: 7633–7643.

64. Okamoto M, Baba H, Goldstein PA, Higashi H, Shimoji K, et al. (2001) Functional reorganization of sensory pathways in the rat spinal dorsal horn following peripheral nerve injury. J Physiol 532: 241–250

65. Woolf CJ, Reynolds ML, Chong MS, Emson P, Irwin N, et al. (1992) Denervation of the motor endplate results in the rapid expression by terminal Schwann cells of the growth-associated protein GAP-43. J Neurosci 12: 3999–4010.