Inhibition of IL-6 signaling

A novel therapeutic approach to treating spinal cord injury pain

Jutatip Guptarak, Sheshali Wanchoo, Julieann Durham-Lee, Yewen Wu, Dragoslava Zivadinovic, Adriana Paulucci-Holthauzen, Olivera Nesic

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

To characterize the contribution of interleukin-6 (IL-6) to spinal cord injury pain (SCIP), we employed a clinically relevant rat contusion model of SCIP. Using Western blots, we measured IL-6 levels in lumbar segments (L1-L5), at the lesion site (T10), and in the corresponding lumbar and thoracic dorsal root ganglia (DRG) in 2 groups of similarly injured rats: (a) SCI rats that developed hind-limb mechanical allodynia (SCIP), and (b) SCI rats that did not develop SCIP. Only in SCIP rats did we find significantly increased IL-6 levels. Immunocytochemistry showed elevated IL-6 predominantly in reactive astrocytes. Our data also showed that increased production of IL-6 in hyperreactive astrocytes in SCIP rats may explain still-poorly understood astrocytic contribution to SCIP. To test the hypothesis that IL-6 contributes to mechanical allodynia, we treated SCIP rats with neutralizing IL-6 receptor antibody (IL-6-R Ab), and found that one systemic injection abolished allodynia and associated weight loss; in contrast to gabapentin, the analgesic effect lasted for at least 2 weeks after the injection, despite the shorter presence of the Ab in the circulation. We also showed that IL-6-R Ab partially reversed SCI-induced decreases in the protein levels of the glutamate transporter GLT-1 12 hours and 8 days after Ab injection, which may explain the lasting analgesic effect of the Ab in SCIP rats. A link between reactive astrocytes IL-6-GLT-1 has not been previously shown. Given that the humanized IL-6-R Ab tocilizumab is Food and Drug Administration-approved for rheumatoid arthritis, we are proposing tocilizumab as a novel and potentially effective treatment for SCIP.

Original languageEnglish (US)
Pages (from-to)1115-1128
Number of pages14
JournalPain
Volume154
Issue number7
DOIs
StatePublished - Jan 1 2013

Fingerprint

Spinal Cord Injuries
Interleukin-6
Pain
Hyperalgesia
Astrocytes
Therapeutics
Injections
Analgesics
Inhibition (Psychology)
Amino Acid Transport System X-AG
Interleukin-6 Receptors
Contusions
Spinal Ganglia
United States Food and Drug Administration
Weight Loss
Rheumatoid Arthritis
Thorax
Extremities
Western Blotting
Immunohistochemistry

Keywords

  • Astrocytes
  • Body weight
  • Gabapentin
  • GLT-1
  • gp130
  • Interleukin 6 receptor antibody
  • Mechanical allodynia
  • Spinal cord injury pain

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Guptarak, J., Wanchoo, S., Durham-Lee, J., Wu, Y., Zivadinovic, D., Paulucci-Holthauzen, A., & Nesic, O. (2013). Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain. Pain, 154(7), 1115-1128. https://doi.org/10.1016/j.pain.2013.03.026

Inhibition of IL-6 signaling : A novel therapeutic approach to treating spinal cord injury pain. / Guptarak, Jutatip; Wanchoo, Sheshali; Durham-Lee, Julieann; Wu, Yewen; Zivadinovic, Dragoslava; Paulucci-Holthauzen, Adriana; Nesic, Olivera.

In: Pain, Vol. 154, No. 7, 01.01.2013, p. 1115-1128.

Research output: Contribution to journalArticle

Guptarak, J, Wanchoo, S, Durham-Lee, J, Wu, Y, Zivadinovic, D, Paulucci-Holthauzen, A & Nesic, O 2013, 'Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain', Pain, vol. 154, no. 7, pp. 1115-1128. https://doi.org/10.1016/j.pain.2013.03.026
Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A et al. Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain. Pain. 2013 Jan 1;154(7):1115-1128. https://doi.org/10.1016/j.pain.2013.03.026
Guptarak, Jutatip ; Wanchoo, Sheshali ; Durham-Lee, Julieann ; Wu, Yewen ; Zivadinovic, Dragoslava ; Paulucci-Holthauzen, Adriana ; Nesic, Olivera. / Inhibition of IL-6 signaling : A novel therapeutic approach to treating spinal cord injury pain. In: Pain. 2013 ; Vol. 154, No. 7. pp. 1115-1128.
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