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Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy

  • Johannes Gjerstad EMAIL logo
Published/Copyright: January 1, 2016
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 10 Issue 1

Neuropathic pain following nerve injury may have clinical manifestations such as hyperalgesia, allodynia and spontaneous pain [1]. This can be a result of hyperexcitability in peripheral nerve fibres, but may also involve induction of long-term potentiation (LTP) in the CNS. In this issue of the Scandinavian Journal of Pain, Bojovic and coworkers address the possible role of changes in the immediate early gene proteins (IEGPs) Arc, Zif268 and c-Fos expression in the dorsal horn during neuropathic pain following noxious conditioning stimulation of the sciatic nerve [2]. The aim of the study was to compare the effect of this noxious conditioning in neuropathic rats versus non-neuropathic rats.

Previously, Bojovic and coworkers have shown that the noxious conditioning changes the expression of the IEGP mentioned above [3], as well as induce spinal cord LTP [4]. Earlier data suggest that the LTP phenomenon induced by noxious stimuli represents a cellular memory of nociceptive information. Several lines of evidence show that extracellular signal-regulated kinase (ERK) is activated in the dorsal horn neurons following noxious sciatic nerve stimulation [5]. ERK can be translocated to the nucleus where it activates the cAMP element binding protein (CREB), which in turn stimulates transcription by binding to the regulatory cAMP response element (CRE). Many IEGPs including Arc, Zif268 and c-Fos may be induced by the ERK-CREB pathway.

The IEGP responses are complex and may include induction of many different transcription factors as well as growth factors, signalling enzymes, phosphatases and structural proteins. Since the late-phase LTP in the dorsal horn may be blocked by protein synthesis inhibitors [6], it seems likely that maintenance of LTP in the spinal cord involves de novo protein synthesis. A primary nuclear event in this process may be the induction of IEGs. Evidence exists that peripheral inflammation also increases the expression of the CRE-containing IEGs in the spinal cord [7].

The results of Bojovic and coworkers showed that Arc, Zif268 and c-Fos exhibited a significant increase in the dorsal horn immunoreactivity the first hours after the sciatic conditioning compared with time-matched, sham operated controls. As in previous reports [3], the authors show that maximal IEGP expression may be found 2 h after the conditioning. Interestingly, the increase in IEGPs following sciatic conditioning was more pronounced in the neuropathic rats than in the non-neuropathic rats. If this up-regulation of the IEGPs induces spinal hyperexcitability, these data indicate that noxious input after nerve injury through the IEGPs may result in increased susceptibility to further noxious stimuli.

The study of Bojovic and coworkers may be informative for both basic scientists and clinicians interested in neuropathic pain. However, whether or not induction of spinal cord LTP induced by the experimental conditioning stimulation of the sciatic nerve really is relevant for sensitization in patients may be debated. Moreover, the authors have not directly examined the relationship between the changes in the IEGPs and development or maintenance of neuropathic pain, only demonstrated an up-regulation of three IEGPs. Hence, when it comes to the clinical interpretations, the study has clear limitations, which also are emphasized by the authors in their discussion [2].

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.09.002.

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  1. Conflict of interest: The author declares no conflict of interest.

References

[1] Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524–34.Search in Google Scholar

[2] Bojovic O, Bramham CR, Tjolsen A. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy. Scand J Pain 2016. pii:S1877-8860 (15) 00095–6.Search in Google Scholar

[3] Bojovic O, Panja D, Bittins M, Bramham CR, Tjolsen A. Time course of immediate early gene protein expression in the spinal cord following conditioning stimulation of the sciatic nerve in rats. PLOS ONE 2015;10:e0123604.Search in Google Scholar

[4] Haugan F, Wibrand K, Fiska A, Bramham CR, Tjolsen A. Stability of long term facilitation and expression of zif268 and Arc in the spinal cord dorsal horn is modulated by conditioning stimulation within the physiological frequency range of primary afferent fibers. Neuroscience 2008;154:1568–75.Search in Google Scholar

[5] Lever IJ, Pezet S, McMahon SB, Malcangio M. The signaling components of sensory fiber transmission involved in the activation of ERK MAP kinase in the mouse dorsal horn. Mol Cell Neurosci 2003;24:259–70.Search in Google Scholar

[6] Hu NW, Zhang HM, Hu XD, Li MT, Zhang T, Zhou LJ, Liu XG. Protein synthesis inhibition blocks the late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 2003;89:2354–9.Search in Google Scholar

[7] Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471–5.Search in Google Scholar
Published Online: 2016-01-01
Published in Print: 2016-01-01

© 2015 Scandinavian Association for the Study of Pain

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https://doi.org/10.1016/j.sjpain.2015.09.006

Articles in the same Issue

  1. Editorial comment
  2. Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain
  3. Original experimental
  4. Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study
  5. Editorial comment
  6. Genetic variability of pain – A patient focused end-point
  7. Observational study
  8. COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain
  9. Editorial comment
  10. Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options
  11. Clinical pain research
  12. Complex regional pain syndrome following viper-bite
  13. Editorial comment
  14. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers
  15. Original experimental
  16. An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants
  17. Editorial comment
  18. Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions – The need for quality control with follow-up studies of patient outcomes
  19. Observational study
  20. Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic
  21. Editorial comment
  22. Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions
  23. Clinical pain research
  24. Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects
  25. Editorial comment
  26. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  27. Original experimental
  28. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy
  29. Editorial comment
  30. Targeting glial dysfunction to treat post-surgical neuropathic pain
  31. Topical review
  32. Glial dysfunction and persistent neuropathic postsurgical pain
  33. Editorial comment
  34. Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain
  35. Original experimental
  36. Impaired recognition memory and cognitive flexibility in the ratL5–L6 spinal nerve ligation model of neuropathic pain
  37. Editorial comment
  38. Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option
  39. Original experimental
  40. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models
  41. Editorial comment
  42. The obesity epidemic makes life difficult for patients with herniated lumbar discs – and for back-surgeons: Increased risk of complications
  43. Observational study
  44. Obesity has an impact on outcome in lumbar disc surgery
  45. Editorial comment
  46. Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain
  47. Clinical pain research
  48. Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ)
  49. Editorial comment
  50. Pain, sleep and catastrophizing: The conceptualization matters Comment on Wilt JA et al. “A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients”
  51. Clinical pain research
  52. A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients
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