Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Scandinavian Journal of Pain

Official Journal of the Scandinavian Association for the Study of Pain

Editor-in-Chief: Werner, Mads

CiteScore 2018: 0.85

SCImago Journal Rank (SJR) 2018: 0.494
Source Normalized Impact per Paper (SNIP) 2018: 0.427

See all formats and pricing
More options …
Volume 16, Issue 1


Effect of intrathecal glucocorticoids on the central glucocorticoid receptor in a rat nerve ligation model

Mienke Rijsdijk / Nilesh M. Agalave / Albert J.M. van Wijck / Cornelis J. Kalkman / Roshni Ramachandran / Azar Baharpoor / Camilla I. Svensson / Tony L. Yaksh
Published Online: 2017-07-01 | DOI: https://doi.org/10.1016/j.sjpain.2016.12.008


Background and aims

Despite widespread use, the efficacy of neuraxial glucocorticoids for neuropathic painis subject to debate. Since most glucocorticoid actions are mediated through its receptor, we explored the effects of intrathecal methylprednisolone acetate (MPA) on total glucocorticoid receptor (tGR) levels and activation of the glucocorticoid receptor (phosphorylated state = pGR) within the spinal dorsal horn (SDH) and dorsal root ganglion (DRG) in a spinal nerve ligation (SNL) model in rats.


Rats received unilateral ligation of the L5/L6 spinal nerves and were treated with two intrathecal doses of either 400 μg MPA or 0.9% saline with a 72-h interval. Plantar tactile thresholds were measured over time. Seven days after drug treatment, DRG and SDH were harvested to assess tGR and pGR levels using immunohistochemistry and qPCR.


Allodynia, defined by lowered tactile withdrawal thresholds after SNL, was unaltered by intrathecal MPA. In saline controls, mRNA levels of tGR did not change after SNL in the DRGs or SDH. tGR and pGR protein levels in the SDH however, significantly increased on the ipsilateral side of SNL compared to the contralateral side and to naïve tissue. When treating rats with MPA, tGR mRNA levels were significantly reduced in the SDH compared to saline controls. tGR and pGR protein levels, however were not significantly lower compared to saline controls.


In intrathecal MPA treated rats, tGR mRNA levels decreased after SNL. However this did not result in lower tGR and pGR protein levels compared to saline controls, and did not decrease ligation-induced mechanical hypersensitivity.


Intrathecal MPA treatment after SNL did not result in lower tGR and pGR levels within the SDH and DRG compared to saline controls. In present study we did not differentiate between the various isoforms of the GR which might clarify this finding.

Keywords: Intrathecal; Methylprednisolone acetate; Spinal nerve ligation; Mechanical allodynia; Glucocorticoid receptor; Rats


  • [1]

    Mensah-Nyagan AG, Meyer L, Schaeffer V, Kibaly C, Patte-Mensah C. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology 2009;34(Suppl. 1):S169–77.PubMedCrossrefGoogle Scholar

  • [2]

    Cohen SP, Bicket MC, Jamison D, Wilkinson I, Rathmell JP. Epidural steroids: a comprehensive, evidence-based review. Reg Anesth Pain Med 2013;38:175–200.CrossrefPubMedGoogle Scholar

  • [3]

    Gu X, Peng L, Yang D, Ma Q, Zheng Y, Liu C, Zhu B, Song L, Sun X, Ma Z. The respective and interaction effects of spinal GRs and MRs on radicular pain induced by chronic compression of the dorsal root ganglion in the rat. Brain Res 2011;1396:88–95.Web of ScienceCrossrefPubMedGoogle Scholar

  • [4]

    Ma ZL, Zhang W, Gu XP, Yang WS, Zeng YM. Effects of intrathecal injection of prednisolone acetate on expression of NR2B subunit and nNOS in spinal cord of rats after chronic compression of dorsal root ganglia. Ann Clin Lab Sci 2007;37:349–55.PubMedGoogle Scholar

  • [5]

    Munts AG, van der Plas AA, Ferrari MD, Teepe-Twiss IM, Marinus J, van Hilten JJ. Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome. Eur J Pain 2010;14:523–8.CrossrefPubMedWeb of ScienceGoogle Scholar

  • [6]

    Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ. No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;17:714–23.CrossrefPubMedWeb of ScienceGoogle Scholar

  • [7]

    Scholz J, Abele A, Marian C, Haussler A, Herbert TA, Woolf CJ, Tegeder I. Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats. Pain 2008;138: 130–42.Web of SciencePubMedCrossrefGoogle Scholar

  • [8]

    Takeda K, Sawamura S, Sekiyama H, Tamai H, Hanaoka K. Effect of methylprednisolone on neuropathic pain and spinal glial activation in rats. Anesthesiology 2004;100:1249–57.CrossrefPubMedGoogle Scholar

  • [9]

    Wang QS, Jiang YH, Wang TD, Xiao T, Wang JK. Effects of betamethasone on neuropathic pain in a rat spare nerve injury model. Clin Exp Pharmacol Physiol 2013;40:22–7.Web of ScienceCrossrefGoogle Scholar

  • [10]

    Wang S, Lim G, Zeng Q, Sung B, Ai Y, Guo G, Yang L, Mao J. Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J Neurosci 2004;24: 8595–605.CrossrefPubMedGoogle Scholar

  • [11]

    Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514–9.CrossrefPubMedGoogle Scholar

  • [12]

    Rijsdijk M, Svensson CI, van Wijck AJM, Kalkman CJ, Yaksh TL. Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models. Scan J Pain 2016;10:90–102.Google Scholar

  • [13]

    Rijsdijk M, van Wijck AJ, Kalkman CJ, Yaksh TL. The effects of glucocorticoids on neuropathic pain: a review with emphasis on intrathecal methylprednisolone acetate delivery. Anesth Analg 2014;118:1097–112.Web of SciencePubMedCrossrefGoogle Scholar

  • [14]

    Yan P, Xu J, Li Q, Chen S, Kim GM, Hsu CY, Xu XM. Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 1999;19:9355–63.CrossrefPubMedGoogle Scholar

  • [15]

    Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355–63.CrossrefPubMedGoogle Scholar

  • [16]

    Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55–63.CrossrefPubMedGoogle Scholar

  • [17]

    Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–6.CrossrefPubMedGoogle Scholar

  • [18]

    Rijsdijk M, van Wijck AJ, Kalkman CJ, Meulenhoff PC, Grafe MR, Steinauer J, Yaksh TL. Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs. Anesthesiology 2012;116:170–81.Web of ScienceCrossrefPubMedGoogle Scholar

  • [19]

    Dschietzig T, Bartsch C, Wessler S, Baumann G, Stangl K. Autoregulation of human relaxin-2 gene expression critically involves relaxin and glucocorticoid receptor binding to glucocorticoid response half-sites in the relaxin-2 promoter. Regul Pept 2009;155:163–73.Web of ScienceCrossrefPubMedGoogle Scholar

  • [20]

    Wang Z, Frederick J, Garabedian MJ. Deciphering the phosphorylation “code” of the glucocorticoid receptor in vivo. J Biol Chem 2002;277:26573–80.CrossrefPubMedGoogle Scholar

  • [21]

    Arkhipova SS, Raginov IS, Mukhitov AR, Chelyshev YA. Satellite cells of sensory neurons after various types of sciatic nerve trauma in the rat. Neurosci Behav Physiol 2010;40:609–14.PubMedCrossrefGoogle Scholar

  • [22]

    DuBois DC, Sukumaran S, Jusko WJ, Almon RR. Evidence for a glucocorticoid receptor beta splice variant in the rat and its physiological regulation in liver. Steroids 2013;78:312–20.CrossrefPubMedWeb of ScienceGoogle Scholar

  • [23]

    Boyle DL, Rosengren S, Bugbee W, Kavanaugh A, Firestein GS. Quantitative biomarker analysis of synovial gene expression by real-time PCR. Arthritis Res Ther 2003;5:R352–60.Google Scholar

  • [24]

    Takasaki I, Kurihara T, Saegusa H, Zong S, Tanabe T. Effects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain. Eur J Pharmacol 2005;524:80–3.CrossrefPubMedGoogle Scholar

  • [25]

    Zhang J, Zhang W, Sun Y, Liu Y, Song L, Ma Z, Gu X. Activation of GRs-Akt-nNOs-NR2B signaling pathway by second dose GR agonist contributes to exacerbated hyperalgesia in a rat model of radicular pain. Mol Biol Rep 2014;41:4053–61.Web of ScienceCrossrefGoogle Scholar

  • [26]

    Nicolaides NC, Charmandari E, Chrousos GP, Kino T. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor. BMC Endocr Disord 2014;14:71.PubMedWeb of ScienceCrossrefGoogle Scholar

  • [27]

    Lu NZ, Cidlowski JA. Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 2006;16:301–7.CrossrefPubMedGoogle Scholar

  • [28]

    Galliher-Beckley AJ, Cidlowski JA. Emerging roles of glucocorticoid receptor phosphorylation in modulating glucocorticoid hormone action in health and disease. IUBMB Life 2009;61:979–86.Web of SciencePubMedCrossrefGoogle Scholar

  • [29]

    Fuxe K, Harfstrand A, Agnati LF, Yu ZY, Cintra A, Wikstrom AC, Okret S, Cantoni E, Gustafsson JA. Immunocytochemical studies on the localization of glucocorticoid receptor immunoreactive nerve cells in the lower brain stem and spinal cord of the male rat using a monoclonal antibody against rat liver glucocorticoid receptor. Neurosci Lett 1985;60:1–6.CrossrefPubMedGoogle Scholar

About the article

Pain Clinic, Department of Anesthesiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Received: 2016-04-03

Revised: 2016-12-30

Accepted: 2016-12-31

Published Online: 2017-07-01

Published in Print: 2017-07-01

Conflict of interest: None.

Authors’ contribution: M. Rijsdijk performed the research, R. Ramachandran, N.M. Agalave and A. Baharpoor participated in data collection, M Rijsdijk, T.L. Yaksh and C.I. Svensson designed the research study, C.I. Svensson, C.J. Kalkman and T.L. Yaksh contributed essential reagents and tools, M. Rijsdijk, C.I. Svensson, A.J.M. van Wijck, C.J. Kalkman and T.L. Yaksh analyzed the data, M. Rijsdijk wrote the paper and C.I. Svensson, A.J.M. van Wijck, C.J. Kalkman, R. Ramachandran, N.M. Agalave and T.L. Yaksh revised the manuscript. All authors approved the final manuscript.

Citation Information: Scandinavian Journal of Pain, Volume 16, Issue 1, Pages 1–9, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1016/j.sjpain.2016.12.008.

Export Citation

© 2017 Scandinavian Association for the Study of Pain.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Imke Rudnik-Jansen, Karin Schrijver, Nina Woike, Anna Tellegen, Sabine Versteeg, Pieter Emans, George Mihov, Jens Thies, Niels Eijkelkamp, Marianna Tryfonidou, and Laura Creemers
Drug Delivery, 2019, Volume 26, Number 1, Page 226
Shaimaa I. A. Ibrahim, Wenrui Xie, Judith A. Strong, Raquel Tonello, Temugin Berta, and Jun-Ming Zhang
Frontiers in Cellular Neuroscience, 2018, Volume 12

Comments (0)

Please log in or register to comment.
Log in