Skip to main content

Advertisement

SpringerLink
Log in

The effect of serotonin–noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Introduction

Neuropathic pain, commonly related to intervertebral disk (IVD) degeneration, responds poorly to standard pain treatments. Serotonin–noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce neuropathic pain; however their effect on radiculopathy induced by lumbar disk herniation remains unclear. The aim of this study was to investigate the effect of SNRI duloxetine in rat model of IVD-related neuropathic pain.

Materials and methods

Effects of SNRI duloxetine were tested in Sprague–Dawley rats (n = 135). Neuropathic pain was induced by applying autologous nucleus pulposus (NP) on the left L5 dorsal root ganglion (DRG). Duloxetine in concentrations 0.4 mg/kg (low dose) and 1.2 mg/kg (high dose) or saline were administered orally for 10 days. Von Frey test was carried out on post-operative days 2, 7, 14, 21, and 28 to test pain sensitivity. Immunohistochemistry of L5 DRG and L5 segment of spinal cord (SC) was performed on days 7 and 21 to examine expressions of tumor necrosis factor alpha (TNF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ionized calcium-binding adapter molecule 1 (Iba1). On days 14, 21, and 28, expressions of TNF in DRG as well as NGF and BDNF in SC were tested by immunoblotting. Sham-operated rats and naive rats were used as controls.

Results

Duloxetine in both concentrations significantly improved pain threshold from postoperative day 21 onward, compared to the NP + saline group (p < 0.05). High-dose duloxetine significantly inhibited the expression of TNF in DRG (day 28, p < 0.05). Both duloxetine concentrations reduced the expression of NGF in SC (day 21, p < 0.05), but the expression of BDNF remained unchanged.

Conclusion

SNRI duloxetine inhibited neuropathic pain in rats possibly via down-regulating TNF, NGF, and microglia activation. We conclude that duloxetine, and most likely other SNRIs, may be used for the management of lumbar neuropathic pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aoki Y, Rydevik B, Kikuchi S et al (2002) Local applications of disc-related cytokines on spinal nerve roots. Spine 27:1614–1617

    Article  PubMed  Google Scholar 

  2. Aoki Y, Nakajima A, Ohtori S et al (2014) Increase of nerve growth factor levels in the human herniated intervertebral disc: can annular rupture trigger discogenic back pain? Arthritis Res Ther 16:R159

    Article  PubMed  PubMed Central  Google Scholar 

  3. Beggs S, Trang T, Salter MW (2012) P2X4R + microglia drive neuropathic pain. Nat Neurosci 15:1068–1073

    Article  CAS  PubMed  Google Scholar 

  4. Bonnefont J, Chapuy E, Clottes E et al (2005) Spinal 5-HT1A receptors differentially influence nociceptive processing according to the nature of the noxious stimulus in rats: effect of WAY-100635 on the antinociceptive activities of paracetamol, venlafaxine and 5-HT. Pain 114:482–490

    Article  CAS  PubMed  Google Scholar 

  5. Bouhassira D, Lanteri-Minet M, Attal N et al (2008) Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136:380–387

    Article  PubMed  Google Scholar 

  6. Bowsher D (1997) The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline. A randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 13:327–331

    Article  CAS  PubMed  Google Scholar 

  7. Chizh BA, Illes P (2001) P2X receptors and nociception. Pharmacol Rev 53:553–568

    CAS  PubMed  Google Scholar 

  8. Cho HJ, Kim SY, Park MJ et al (1997) Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation. Brain Res 749:358–362

    Article  CAS  PubMed  Google Scholar 

  9. Gilron I, Watson CP, Cahill CM et al (2006) Neuropathic pain: a practical guide for the clinician. CMAJ 175:265–275

    Article  PubMed  PubMed Central  Google Scholar 

  10. Goldstein DJ, Lu Y, Detke MJ et al (2005) Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116:109–118

    Article  CAS  PubMed  Google Scholar 

  11. Graff-Radford SB, Shaw LR, Nailboff BN (2000) Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Clin J Pain 16:188–192

    Article  CAS  PubMed  Google Scholar 

  12. Gyoneva S, Traynelis SF (2013) Norepinephrine modulates the motility of resting and activated microglia via different adrenergic receptors. J Biol Chem 288:15291–15302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hashizume H, Kawakami M, Yoshida M et al (2007) Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, attenuates neurogenic pain induced by nucleus pulposus in rats. Spine 32:315–320

    Article  PubMed  Google Scholar 

  14. Igarashi T, Kikuchi S, Shuvayev V et al (2000) Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine 25:2975–2980

    Article  CAS  PubMed  Google Scholar 

  15. Ito T, Ohtori S, Inoue G et al (2007) Glial phosphorylated p38 MAP kinase mediates pain in a rat model of lumbar disc herniation and induces motor dysfunction in a rat model of lumbar spinal canal stenosis. Spine 32:159–167

    Article  PubMed  Google Scholar 

  16. Kato K, Kikuchi S, Konno S et al (2008) Participation of 5-hydroxytryptamine in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats. Spine 33:1330–1336

    Article  PubMed  Google Scholar 

  17. Kawakami M, Tamaki T, Weinstein JN et al (1996) Pathomechanism of pain-related behavior produced by allografts of intervertebral disc in the rat. Spine 21:2101–2107

    Article  CAS  PubMed  Google Scholar 

  18. Kayama S, Konno S, Olmarker K et al (1996) Incision of the anulus fibrosus induces nerve root morphologic, vascular, and functional changes. An experimental study. Spine 21:2539–2543

    CAS  PubMed  Google Scholar 

  19. Kennedy C, Assis TS, Currie AJ et al (2003) Crossing the pain barrier: P2 receptors as targets for novel analgesics. J Physiol 553:683–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Khakh BS, Burnstick G, Kennedy C et al (2001) International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev 53:107–118

    CAS  PubMed  Google Scholar 

  21. Krabbe G, Matyash V, Pannasch U et al (2012) Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun 26:419–428

    Article  CAS  PubMed  Google Scholar 

  22. Krupkova O, Sekiguchi M, Klasen J et al (2014) Epigallocatechin 3-gallate suppresses interleukin-1β-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats. Eur Cell Mater 28:372–386

    CAS  PubMed  Google Scholar 

  23. Loeser JD, Treede RD (2008) The Kyoto protocol of IASP basic pain terminology. Pain 137:473–477

    Article  PubMed  Google Scholar 

  24. Max MB, Schafer SC, Culnane M et al (1988) Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 38:1427–1432

    Article  CAS  PubMed  Google Scholar 

  25. Max MB, Lynch SA, Muir J et al (1992) Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250–1256

    Article  CAS  PubMed  Google Scholar 

  26. McCarron RF, Wimpee MW, Hudkins PG et al (1987) The inflammatory effect of nucleus pulposus. A possible element in the pathogenesis of low-back pain. Spine 12:760–764

    Article  CAS  PubMed  Google Scholar 

  27. Michael GJ, Averill S, Nitkunan A 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

    CAS  PubMed  Google Scholar 

  28. Micó JA, Ardid D, Beffocoso E et al (2006) Antidepressants and pain. Trends Pharmacol Sci 27:348–354

    Article  PubMed  Google Scholar 

  29. Miyoshi S, Sekiguchi M, Konno S et al (2011) Increased expression of vascular endothelial growth factor protein in dorsal root ganglion exposed to nucleus pulposus on the nerve root in rats. Spine 36:E1–E6

    Article  PubMed  Google Scholar 

  30. Nagata K, Imai T, Yamada T et al (2009) Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief. Mol Pain. doi:10.1186/1744-8069-5-20

    Google Scholar 

  31. Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equine nerve roots. Spine 18:1425–1432

    Article  CAS  PubMed  Google Scholar 

  32. Olmarker K, Brisby H, Yabuki S et al (1997) The effects of normal, frozen, and hyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine 22:471–476

    Article  CAS  PubMed  Google Scholar 

  33. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine 23:2538–2544

    Article  CAS  PubMed  Google Scholar 

  34. Onda A, Murata Y, Rydevik B et al (2003) Immunoreactivity of brain-derived neurotrophic factor in rat dorsal root ganglion and spinal cord dorsal horn following exposure to herniated nucleus pulposus. Neurosci Lett 352:49–52

    Article  CAS  PubMed  Google Scholar 

  35. Otoshi K, Kikuchi S, Konno S et al (2010) The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain- related behavior after application of nucleus pulpose onto the nerve in rats. Spine 35:264–271

    Article  PubMed  Google Scholar 

  36. Otoshi K, Kikuchi S, Kato K et al (2011) Anti-HMGB1 neutralization antibody improves pain-related behavior induced by application of autologous nucleus pulposus onto nerve roots in rats. Spine 36:E692–E698

    Article  PubMed  Google Scholar 

  37. Peng B, Wu W, Li Z et al (2007) Chemical radiculitis. Pain 127:11–16

    Article  CAS  PubMed  Google Scholar 

  38. Raskin J, Pritchett YL, Wang F (2005) A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 6:346–356

    Article  PubMed  Google Scholar 

  39. Saarto T, Wiffen PJ (2010) Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiarty 81:1372–1373

    Article  Google Scholar 

  40. Saito H, Wakai J, Sekiguchi M et al (2014) The effect of selective serotonin reuptake inhibitor (SSRI) on pain-related behavior in a rat model of neuropathic pain. Eur Spine J 23:2401–2409

    Article  PubMed  Google Scholar 

  41. Sasaki N, Kikuchi S, Konno S et al (2007) Anti-TNF-alpha antibody reduces pain-behavior changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine 32:413–416

    Article  PubMed  Google Scholar 

  42. Sekiguchi M, Otoshi K, Kikuchi S et al (2011) Analgesic effects of prostaglandin E2 receptor subtype EP1 receptor antagonist: experimental study of application of nucleus pulposus. Spine 36:1829–1834

    Article  PubMed  Google Scholar 

  43. Sindrup SH, Gram LF, Brosen K et al (1990) The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42:135–144

    Article  CAS  PubMed  Google Scholar 

  44. Smith EM, Pang H, Cirrincione C et al (2013) Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 309:1359–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tachihara H, Sekiguchi M, Kikuchi S et al (2008) Do corticosteroids produce additional benefit in nerve root infiltration for lumbar disc herniation? Spine 33:743–747

    Article  PubMed  Google Scholar 

  46. Takahashi K, Aoki Y, Ohtori S (2008) Resolving discogenic pain. Eur Spine J. doi:10.1007/s00586-008-0752-4

    PubMed  PubMed Central  Google Scholar 

  47. 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

    Article  CAS  PubMed  Google Scholar 

  48. Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci 28:101–107

    Article  CAS  PubMed  Google Scholar 

  49. Urani A, Chourbaji S, Gass P (2005) Mutant mouse models of depression: candidate genes and current mouse lines. Neurosci Biobehav Rev 29:805–828

    Article  CAS  PubMed  Google Scholar 

  50. Vollmar P, Haghikia A, Dermietzel R et al (2008) Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model. Int J Neuropsychopharmacol 11(1):111–117

    Article  CAS  PubMed  Google Scholar 

  51. Wernicke JF, Pritchett YL, D’Souza DN et al (2006) A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67:1411–1420

    Article  CAS  PubMed  Google Scholar 

  52. Weurtz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, Kikuchi S, Boos N (2011) The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine 36(21):E1373–E1384

    Article  Google Scholar 

  53. Woolf CJ, Allchrone A, Safieh-Garabedian B et al (1997) Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol 121:417–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yasuda H, Hotta N, Nakao K et al (2011) Superiority of duloxetine to placebo in improving diabetic neuropathic pain. Results of a randomized controlled trial in Japan. J Diabetes Investig 2:132–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yokogawa F, Kikuchi Y, Ishikawa Y et al (2002) An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg 95:163–168

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Akira Sato and Kazuo Sasaki for their technical assistance.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan

    Junichi Handa, Miho Sekiguchi & Shin-ichi Konno

  2. Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland

    Olga Krupkova

Authors
  1. Junichi Handa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miho Sekiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olga Krupkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shin-ichi Konno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miho Sekiguchi.

Ethics declarations

Conflict of interest

There is no potential conflict in this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Handa, J., Sekiguchi, M., Krupkova, O. et al. The effect of serotonin–noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats. Eur Spine J 25, 877–887 (2016). https://doi.org/10.1007/s00586-015-4239-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-015-4239-9

Keywords

Search

Navigation