Advertisement

Hypothalamic–pituitary–adrenal axis function in traumatic spinal cord injury-related neuropathic pain: a case–control study

  • E. Cuce
  • H. Demir
  • I. Cuce
  • F. Bayram
Original Article

Abstract

Purpose

This study aimed to investigate the hypothalamic–pituitary–adrenal (HPA) axis in spinal cord injury (SCI)-related neuropathic pain (NP) using dynamic adrenocorticotropic hormone (ACTH) stimulation tests.

Methods

This case–control study was conducted with 22 patients diagnosed with traumatic chronic spinal cord injury (15 with and 7 without neuropathic pain) and ten age- and sex-matched healthy control subjects. Collected data included socio-demographic variables, SCI characteristics, and level of NP using a numeric rating scale (NRS) and the Leeds Assessment of Neuropathic Symptoms and Signs pain scale (LANSS). HPA axis function was measured via low-dose (1 μg) and standard-dose (250 μg) ACTH tests (LDT and SDT, respectively).

Results

No significant differences existed regarding peak cortisol responses or area under the curve (AUC) of cortisol responses between the SCI patients with NP and healthy controls using LDT and SDT. In the SCI patients without pain, cortisol responses were significantly lower than those in the healthy controls for LDT and SDT. Peak cortisol and AUC responses of the LDT and SDT were positively correlated with NRS in SCI patients with NP.

Conclusions

This study demonstrated that, in chronic SCI patients with NP, basal cortisol levels are relatively higher compared to healthy controls, and that HPA axis can be activated with low- and standard-dose ACTH stimulation tests. Although NP following SCI was not significantly associated with hypo- or hypercortisolemia, either after low- or standard-dose ACTH stimulation test, the severity of NP during chronic SCI may be positively associated with HPA axis activity.

Keywords

Spinal cord injuries Neuralgia Pain Hypothalamus Pituitary–adrenal system ACTH Glucocorticoids 

Notes

Acknowledgements

This study was supported by a grant from the Research Fund of the Erciyes University (Project Number TTU-2015-5672). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Erciyes University, Faculty of Medicine.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consents were signed by all patients.

References

  1. 1.
    Finnerup NB (2013) Pain in patients with spinal cord injury. Pain 154(Suppl 1):S71–S76.  https://doi.org/10.1016/j.pain.2012.12.007 CrossRefPubMedGoogle Scholar
  2. 2.
    Burke D, Fullen BM, Stokes D, Lennon O (2017) Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur J Pain 21(1):29–44.  https://doi.org/10.1002/ejp.905 CrossRefPubMedGoogle Scholar
  3. 3.
    Muller R, Landmann G, Bechir M, Hinrichs T, Arnet U, Jordan X, Brinkhof MWG (2017) Chronic pain, depression and quality of life in individuals with spinal cord injury: mediating role of participation. J Rehabil Med 49(6):489–496.  https://doi.org/10.2340/16501977-2241 CrossRefPubMedGoogle Scholar
  4. 4.
    Lucin KM, Sanders VM, Jones TB, Malarkey WB, Popovich PG (2007) Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp Neurol 207(1):75–84.  https://doi.org/10.1016/j.expneurol.2007.05.019 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (2017) Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr 75(6):387–393.  https://doi.org/10.1590/0004-282x20170048 CrossRefPubMedGoogle Scholar
  6. 6.
    Yan P, Xu J, Li Q, Chen S, Kim GM, Hsu CY, Xu XM (1999) Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 19(21):9355–9363CrossRefGoogle Scholar
  7. 7.
    Madalena KM, Lerch JK (2016) Glucocorticoids and nervous system plasticity. Neural Regen Res 11(1):37CrossRefGoogle Scholar
  8. 8.
    Wang S, Lim G, Zeng Q, Sung B, Ai Y, Guo G, Yang L, Mao J (2004) Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J Neurosci 24(39):8595–8605.  https://doi.org/10.1523/jneurosci.3058-04.2004 CrossRefPubMedGoogle Scholar
  9. 9.
    Le Coz GM, Anton F, Hanesch U (2014) Glucocorticoid-mediated enhancement of glutamatergic transmission may outweigh anti-inflammatory effects under conditions of neuropathic pain. PLoS One 9(3):e91393.  https://doi.org/10.1371/journal.pone.0091393 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bomholt SF, Mikkelsen JD, Blackburn-Munro G (2005) Normal hypothalamo-pituitary-adrenal axis function in a rat model of peripheral neuropathic pain. Brain Res 1044(2):216–226.  https://doi.org/10.1016/j.brainres.2005.03.005 CrossRefPubMedGoogle Scholar
  11. 11.
    Ulrich-Lai YM, Xie W, Meij JT, Dolgas CM, Yu L, Herman JP (2006) Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol Behav 88(1–2):67–76.  https://doi.org/10.1016/j.physbeh.2006.03.012 CrossRefPubMedGoogle Scholar
  12. 12.
    Kramer JL, Minhas NK, Jutzeler CR, Erskine EL, Liu LJ, Ramer MS (2017) Neuropathic pain following traumatic spinal cord injury: models, measurement, and mechanisms. J Neurosci Res 95(6):1295–1306.  https://doi.org/10.1002/jnr.23881 CrossRefPubMedGoogle Scholar
  13. 13.
    Gwak YS, Hulsebosch CE (2017) Neuronal-glial interactions maintain chronic neuropathic pain after spinal cord injury. Neural Plast 2017:2480689.  https://doi.org/10.1155/2017/2480689 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kirshblum S, Waring W 3rd (2014) Updates for the international standards for neurological classification of spinal cord injury. Phys Med Rehabil Clin N Am 25(3):505–517, vii.  https://doi.org/10.1016/j.pmr.2014.04.001 CrossRefPubMedGoogle Scholar
  15. 15.
    Bryce TN, Biering-Sorensen F, Finnerup NB, Cardenas DD, Defrin R, Lundeberg T, Norrbrink C, Richards JS, Siddall P, Stripling T, Treede RD, Waxman SG, Widerstrom-Noga E, Yezierski RP, Dijkers M (2012) International spinal cord injury pain classification: part I. Background and description. March 6–7, 2009. Spinal Cord 50(6):413–417.  https://doi.org/10.1038/sc.2011.156 CrossRefPubMedGoogle Scholar
  16. 16.
    Bennett M (2001) The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 92(1–2):147–157CrossRefGoogle Scholar
  17. 17.
    Karaca Z, Lale A, Tanriverdi F, Kula M, Unluhizarci K, Kelestimur F (2011) The comparison of low and standard dose ACTH and glucagon stimulation tests in the evaluation of hypothalamo–pituitary–adrenal axis in healthy adults. Pituitary 14(2):134–140.  https://doi.org/10.1007/s11102-010-0270-3 CrossRefPubMedGoogle Scholar
  18. 18.
    Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER (1998) Function of the hypothalamic–pituitary–adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol 25(7):1374–1381PubMedGoogle Scholar
  19. 19.
    Generaal E, Vogelzangs N, Macfarlane GJ, Geenen R, Smit JH, Penninx BW, Dekker J (2014) Reduced hypothalamic–pituitary–adrenal axis activity in chronic multi-site musculoskeletal pain: partly masked by depressive and anxiety disorders. BMC Musculoskelet Disord 15:227.  https://doi.org/10.1186/1471-2474-15-227 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Heim C, Ehlert U, Hanker JP, Hellhammer DH (1998) Abuse-related posttraumatic stress disorder and alterations of the hypothalamic–pituitary–adrenal axis in women with chronic pelvic pain. Psychosom Med 60(3):309–318CrossRefGoogle Scholar
  21. 21.
    Wang YH, Huang TS (1999) Impaired adrenal reserve in men with spinal cord injury: results of low- and high-dose adrenocorticotropin stimulation tests. Arch Phys Med Rehabil 80(8):863–866CrossRefGoogle Scholar
  22. 22.
    Huang TS, Wang YH, Lee SH, Lai JS (1998) Impaired hypothalamus–pituitary–adrenal axis in men with spinal cord injuries. Am J Phys Med Rehabil 77(2):108–112CrossRefGoogle Scholar
  23. 23.
    Park JY, Ahn RS (2012) Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1. Psychoneuroendocrinology 37(9):1557–1568.  https://doi.org/10.1016/j.psyneuen.2012.02.016 CrossRefPubMedGoogle Scholar
  24. 24.
    Allison DJ, Ditor DS (2015) Immune dysfunction and chronic inflammation following spinal cord injury. Spinal Cord 53(1):14–18.  https://doi.org/10.1038/sc.2014.184 CrossRefPubMedGoogle Scholar
  25. 25.
    Davies AL, Hayes KC, Dekaban GA (2007) Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil 88(11):1384–1393.  https://doi.org/10.1016/j.apmr.2007.08.004 CrossRefPubMedGoogle Scholar
  26. 26.
    Straub RH, Bijlsma JW, Masi A, Cutolo M (2013) Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases—the 10-year update. Semin Arthritis Rheum 43(3):392–404.  https://doi.org/10.1016/j.semarthrit.2013.04.008 CrossRefPubMedGoogle Scholar
  27. 27.
    Tenk J, Matrai P, Hegyi P, Rostas I, Garami A, Szabo I, Solymar M, Petervari E, Czimmer J, Marta K, Miko A, Furedi N, Parniczky A, Zsiboras C, Balasko M (2016) In obesity, HPA axis activity does not increase with BMI, but declines with aging: a meta-analysis of clinical studies. PLoS One 11(11):e0166842.  https://doi.org/10.1371/journal.pone.0166842 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Strittmatter M, Grauer MT, Fischer C, Hamann G, Hoffmann KH, Blaes F, Schimrigk K (1996) Autonomic nervous system and neuroendocrine changes in patients with idiopathic trigeminal neuralgia. Cephalalgia 16(7):476–480.  https://doi.org/10.1046/j.1468-2982.1996.1607476.x CrossRefPubMedGoogle Scholar
  29. 29.
    Miller GE, Chen E, Zhou ES (2007) If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull 133(1):25–45.  https://doi.org/10.1037/0033-2909.133.1.25 CrossRefPubMedGoogle Scholar
  30. 30.
    Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B (2016) Regulation of the hypothalamic–pituitary–adrenocortical stress response. Compr Physiol 6(2):603–621.  https://doi.org/10.1002/cphy.c150015 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Takasaki I, Kurihara T, Saegusa H, Zong S, Tanabe T (2005) Effects of glucocorticoid receptor antagonists on allodynia and hyperalgesia in mouse model of neuropathic pain. Eur J Pharmacol 524(1–3):80–83.  https://doi.org/10.1016/j.ejphar.2005.09.045 CrossRefPubMedGoogle Scholar
  32. 32.
    Kim EH, Ryu DH, Hwang S (2011) The expression of corticotropin-releasing factor and its receptors in the spinal cord and dorsal root ganglion in a rat model of neuropathic pain. Anat Cell Biol 44(1):60–68.  https://doi.org/10.5115/acb.2011.44.1.60 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Le Coz GM, Fiatte C, Anton F, Hanesch U (2014) Differential neuropathic pain sensitivity and expression of spinal mediators in Lewis and Fischer 344 rats. BMC Neurosci 15:35.  https://doi.org/10.1186/1471-2202-15-35 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  1. 1.Department of Physical Medicine and RehabilitationAdiyaman University Training and Research HospitalMerkezTurkey
  2. 2.Department of Physical Medicine and Rehabilitation, Faculty of MedicineErciyes UniversityKayseriTurkey
  3. 3.Department of Endocrinology and Metabolism, Faculty of MedicineErciyes UniversityKayseriTurkey

Personalised recommendations