, Volume 27, Issue 1, pp 151–155 | Cite as

Interleukin-1beta in synergism gabapentin with tramadol in murine model of diabetic neuropathy

  • H. F. MirandaEmail author
  • P. Poblete
  • F. Sierralta
  • V. Noriega
  • J. C. Prieto
  • R. J. Zepeda
Original Article


Neuropathic pain is a complication of cancer and diabetes mellitus and the most commonly used drugs in the treatment of the diabetic neuropathic pain have only limited efficacy. The aim of this study was to evaluate the role of the biomarker interleukin-1beta (IL-1ß) in the pharmacological interaction of gabapentin with tramadol in a model of diabetic neuropathic pain. CF-1 male mice, pretreated with 200 mg/kg i.p. of streptozocin (STZ), were used and at day 3 and 7 were evaluated by the hot plate test and the spinal cord level of IL-1ß was determined. Antinociceptive interaction of the coadministration i.p. of gabapentin with tramadol, in basic of the fixed the ratio 1:1 of their ED50 values alone, was ascertained by isobolographic analysis. Tramadol was 1.13 times more potent than gabapentin in saline control mice, 1.40 times in STZ mice at 3 days and 1.28 times in STZ at 7 days. The interaction between gabapentin and tramadol was synergic, with an interaction index of 0.30 and 0.22 for mice pretreated with STZ at 3 and 7 days. The combination of gabapentin with tramadol reversed the increased concentration of IL-1β induced by STZ in diabetic neuropathic mice. These findings could help clarify the mechanism of diabetic neuropathy.


Diabetic neuropathy Gabapentin Tramadol Synergism IL-1ß 



This work was partially supported by the project Fondecyt 11140757, Chile.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.


  1. Bishnoi M, Bosgraaf CA, Abooj M et al (2011) Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators. Mol Pain 7:52–63CrossRefGoogle Scholar
  2. Cheng JK, Chiou LCh (2006) Mechanism of the antinociceptive action of gabapentin. J Pharmacol Sci 100:471–486CrossRefGoogle Scholar
  3. Corona-Ramos JN, De la O-Arciniega M et al (2016) The antinociceptive effects of tramadol and/or gabapentin on rat neuropathic pain induced by a chronic constriction injury. Drug Dev Res 77:217–226CrossRefGoogle Scholar
  4. Dai X, Brunson CD, Rockhold RW et al (2008) Gender differences in the antinociceptive effect of tramadol, alone or in combination with gabapentin, in mice. J Biomed Sci 15:645–651CrossRefGoogle Scholar
  5. Eisenberg E, Suzan E (2014) Drug combinations in the treatment of neuropathic pain. Curr Pain Headache Rep 18:463–470CrossRefGoogle Scholar
  6. Finnerup NB et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173CrossRefGoogle Scholar
  7. King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166:877–894CrossRefGoogle Scholar
  8. Kitada M, Ogura Y, Koya D (2016) Rodent models of diabetic nephropathy: their utility and limitations. Int J Nephrol Renovascular Dis 9:279–290CrossRefGoogle Scholar
  9. Miotto K, Cho AK, Khalil MA et al (2017) Trends on tramadol: pharmacology, metabolism and misuse. Anesth Analg 124:44–51CrossRefGoogle Scholar
  10. Miranda HF, Noriega V, Prieto JC et al (2016) Antinociceptive interaction of tramadol with gabapentin in experimental mononeuropathic pain. Basic Clin Pharmacol Toxicol 119:210–214CrossRefGoogle Scholar
  11. Miranda HF, Sierralta F et al (2017) Antinociceptive interaction of gabapentin with minocycline in murine diabetic neuropathy. Inflammopharmacology 25:91–97CrossRefGoogle Scholar
  12. Muhammad AA, Arulselvan P, Cheah PS et al (2016) Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model. Drug Des Dev Ther 10:1715–1730CrossRefGoogle Scholar
  13. Old EA, Clark AK, Malcangio M (2015) The role of glia in the spinal cord in neuropathic and inflammatory pain. Handb Exp Pharmacol 227:145–170CrossRefGoogle Scholar
  14. Pabreja K, Dua K, Sharma S, Padi SS et al (2011) Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and antioxidant mechanisms. Eur J Pharmacol 661:15–21CrossRefGoogle Scholar
  15. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW et al (2008) Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70:1630–1635CrossRefGoogle Scholar
  16. Vazzana M, Andreani T, Fangueiro J et al (2015) Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother 70:234–238CrossRefGoogle Scholar
  17. Wodarski R, Clark AK, Grist J et al (2009) Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur J Pain 13:807–811CrossRefGoogle Scholar
  18. Zhou J, Zhou S (2014) Inflammation: therapeutic targets for diabetic neuropathy. Mol Neurobiol 49:536–546CrossRefGoogle Scholar
  19. Zychowska M, Rojewska E, Kreiner G et al (2013) Minocycline influences the antiinflammatory interleukins and enhances the effectiveness of morphine under mice diabetic neuropathy. J Neuroimmunol 262:35–45CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • H. F. Miranda
    • 1
    Email author
  • P. Poblete
    • 2
  • F. Sierralta
    • 2
  • V. Noriega
    • 3
  • J. C. Prieto
    • 2
    • 3
  • R. J. Zepeda
    • 1
  1. 1.Neuroscience Department, Faculty of MedicineUniversity of ChileSantiagoChile
  2. 2.Pharmacology Program, ICBM, Faculty of MedicineUniversity of ChileSantiagoChile
  3. 3.Cardiovascular Department, Clinic HospitalUniversity of ChileSantiagoChile

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