Skip to main content
SpringerLink
Log in

Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

Ketamine exerts rapid and robust antidepressant properties in both animal models and depressed patients and tramadol possesses potential antidepressant effects. Brain-derived neurotrophic factor (BDNF) is an important biomarker for mood disorders and tropomyosin-related kinase B (TrkB) is a high affinity catalytic receptor for BDNF.We hypothesized that tramadol pretreatment might reinforce ketamine-elicited antidepressant effects with significant changes in hippocampal BDNF and TrkB levels in rats. Immobility time of rats receiving different treatment in the forced swimming test (FST) was observed. Levels of BDNF and TrkB in hippocampus were measured by enzyme linked immunosorbent assay. Results showed that tramadol (5 mg/kg) administrated alone neither elicited antidepressant effects nor altered BDNF or TrkB level. However, pretreatment with tramadol (5 mg/kg) enhanced the ketamine (10 mg/kg) -elicited antidepressant effects and upregulated the BDNF and TrkB levels in hippocampus. In conclusion, tramadol pretreatment reinforces the ketamine-elicited antidepressant effects, which is associated with the increased levels of BDNF and TrkB in rat hippocampus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71(11): 939–946

    Article  PubMed  CAS  Google Scholar 

  2. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69(8): 754–761

    Article  PubMed  CAS  Google Scholar 

  3. Barber J. Examining the use of tramadol hydrochloride as an antidepressant. Exp Clin Psychopharmacol 2011; 19(2): 123–130

    Article  PubMed  CAS  Google Scholar 

  4. Yalcin I, Aksu F, Bodard S, Chalon S, Belzung C. Antidepressantlike effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system. Behav Pharmacol 2007; 18(7): 623–631

    Article  PubMed  CAS  Google Scholar 

  5. Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64(4): 341–357

    Article  PubMed  CAS  Google Scholar 

  6. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activityantidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res 2001; 120(1): 87–95

    Article  PubMed  CAS  Google Scholar 

  7. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressantlike effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56(1): 131–137

    Article  PubMed  CAS  Google Scholar 

  8. Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J. Acute administration of ketamine induces antidepressant- like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(1): 140–144

    Article  PubMed  CAS  Google Scholar 

  9. Castrén E, Võikar V, Rantamäki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol 2007; 7(1): 18–21

    Article  PubMed  Google Scholar 

  10. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castrén E. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant- induced behavioral effects. J Neurosci 2003; 23(1): 349–357

    PubMed  CAS  Google Scholar 

  11. Rantamäki T, Knuuttila JE, Hokkanen ME, Castrén E. The effects of acute and long-term lithium treatments on TrkB neurotrophin receptor activation in the mouse hippocampus and anterior cingulate cortex. Neuropharmacology 2006; 50(4): 421–427

    Article  PubMed  Google Scholar 

  12. Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 1995; 121(1): 66–72

    Article  CAS  Google Scholar 

  13. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977; 266(5604): 730–732

    Article  PubMed  CAS  Google Scholar 

  14. Jesse CR, Bortolatto CF, Savegnago L, Rocha JB, Nogueira CW. Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(8): 1838–1843

    Article  PubMed  CAS  Google Scholar 

  15. Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 2011; 16(11): 1068–1070

    Article  PubMed  CAS  Google Scholar 

  16. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69(8): 754–761

    Article  PubMed  CAS  Google Scholar 

  17. Bamigbade TA, Davidson C, Langford RM, Stamford JA. Actions of tramadol, its enantiomers and principal metabolite, Odesmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997; 79(3): 352–356

    Article  PubMed  CAS  Google Scholar 

  18. Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M. Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology 1998; 88(3): 768–774

    Article  PubMed  CAS  Google Scholar 

  19. Markowitz JS, Patrick KS. Venlafaxine-tramadol similarities. Med Hypotheses 1998; 51(2): 167–168

    Article  PubMed  CAS  Google Scholar 

  20. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. J Pharmacol Exp Ther 1992; 260(1): 275–285

    PubMed  CAS  Google Scholar 

  21. Valverde O, Micó JA, Maldonado R, Mellado M, Gibert-Rahola J. Participation of opioid and monoaminergic mechanisms on the antinociceptive effect induced by tricyclic antidepressants in two behavioural pain tests in mice. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18(6): 1073–1092

    Article  PubMed  CAS  Google Scholar 

  22. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15(11): 7539–7547

    PubMed  CAS  Google Scholar 

  23. Machado-Vieira R, Yuan P, Brutsche N, DiazGranados N, Luckenbaugh D, Manji HK, Zarate CA Jr. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-Daspartate antagonist. J Clin Psychiatry 2009; 70(12): 1662–1666

    Article  PubMed  CAS  Google Scholar 

  24. Faron-Górecka A, Kuśmider M, Inan SY, Siwanowicz J, Piwowarczyk T, Dziedzicka-Wasylewska M. Long-term exposure of rats to tramadol alters brain dopamine and alpha 1-adrenoceptor function that may be related to antidepressant potency. Eur J Pharmacol 2004; 501(1–3): 103–110

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China

    Chun Yang, Xiaomin Li, Nan Wang, Shixia Xu, Jianjun Yang & Zhiqiang Zhou

Authors
  1. Chun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaomin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shixia Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianjun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhiqiang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhiqiang Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, C., Li, X., Wang, N. et al. Tramadol reinforces antidepressant effects of ketamine with increased levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in rat hippocampus. Front. Med. 6, 411–415 (2012). https://doi.org/10.1007/s11684-012-0226-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-012-0226-2

Keywords

Search

Navigation