Neurochemical Research

, Volume 40, Issue 3, pp 463–472 | Cite as

Curcumin Attenuates CFA Induced Thermal Hyperalgesia by Modulation of Antioxidant Enzymes and Down Regulation of TNF-α, IL-1β and IL-6

  • Ajeet Kumar Singh
  • Manjula VinayakEmail author
Original Paper


Reactive oxygen species are signaling mediators of nociceptive pathways. Exogenous administrations of antioxidants show anti-hyperalgesic effect. However, very little is known about the role of endogenous antioxidant defense system in pain pathology. Curcumin is a dietary antioxidant which shows ameliorative effect on thermal hypersensitivity, however detailed study is lacking. Present study was aimed to analyze the changes in oxidative stress, modulation of antioxidant enzymes and pro-inflammatory cytokines in complete Freund’s adjuvant induced inflammatory hyperalgesia and the effect of curcumin on antioxidant defense system and pro-inflammatory cytokines. Anti-hyperalgesic activity of curcumin was evidenced after 6 h of treatment. Oxidative stress was evidenced in paw skin and spinal cord of hyperalgesic rats by high level of lipid peroxidation. A decrease in activity of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and an increase in level of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in paw skin was observed as compared to normal rats. However, activity of antioxidant enzymes was enhanced in spinal cord. The changes were brought towards normal level after curcumin treatment. The results suggest that modulation of antioxidant defense system is early event in initiation of inflammatory hyperalgesia which might lead to initiation of other signaling pathways mediated by lipid peroxide, TNF-α, IL-1β and IL-6. Decrease in oxidative stress and down regulation of these cytokines by curcumin is suggested to be involved in its anti-hyperalgesic effect.


Lipid peroxidation Inflammatory hyperalgesia ROS Paw skin Spinal cord 



Authors are thankful to DRDO, India for financial support (Grant No. ERIP/ER/1003851/M/01/1336). A.K.S. thanks UGC, India for JRF & SRF.

Conflict of interest



  1. 1.
    Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE et al (2004) Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 111:116–124CrossRefPubMedGoogle Scholar
  2. 2.
    Lee KimHK, Kim JH, Chung K, Chung JM (2007) The role of reactive oxygen species in capsaicin-induced mechanical hyperalgesia and in the activities of dorsal horn neurons. Pain 133:9–17CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Schwartz ES, Lee I, Chung K, Chung JM (2008) Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain 138:514–524CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Jenner P (1994) Oxidative damage in neurodegenerative disease. Lancet 344:796–798CrossRefPubMedGoogle Scholar
  5. 5.
    Tal M (1996) A novel antioxidant alleviates heat hyperalgesia in rats with an experimental painful peripheral neuropathy. NeuroReport 7:1382–1384CrossRefPubMedGoogle Scholar
  6. 6.
    Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E et al (2004) A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther 309:869–878CrossRefPubMedGoogle Scholar
  7. 7.
    Kohli K, Ali J, Ansari MJ, Raheman Z (2005) Curcumin: a natural anti-inflammatory agent. Indian J Pharmacol 37:141–147CrossRefGoogle Scholar
  8. 8.
    Yeon KY, Kim SA, Kim YH, Lee MK, Ahn DK, Kim HJ et al (2010) Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. J Dent Res 89(2):170–174CrossRefPubMedGoogle Scholar
  9. 9.
    Kunchandy E, Rao MNA (1990) Oxygen radical scavenging activity of curcumin. Int Pharm 58:237–240CrossRefGoogle Scholar
  10. 10.
    Sharma S, Kulkarni SK, Agrewala JN, Chopra K (2006) Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pharmacol 536:256–261CrossRefPubMedGoogle Scholar
  11. 11.
    Khattab MM (2006) TEMPOL, a membrane permeable radical scavenger, attenuates peroxynitrite and superoxide anion enhanced carrageenan induced paw edema and hyperalgesia: a key role for superoxide anion. Eur J Pharmacol 548:167–173CrossRefPubMedGoogle Scholar
  12. 12.
    Salvemini D, Wang ZQ, Zweier JL, Samouilov A, Macarthur H, Misko TP et al (1999) A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science 286:304–306CrossRefPubMedGoogle Scholar
  13. 13.
    Keeble JE, Bodkin JV, Liang L (2009) Hydrogen peroxide is a novel mediator of inflammatory hyperalgesia, acting via transient receptor potential vanilloid 1-dependent and independent mechanisms. Pain 141:135–142CrossRefPubMedGoogle Scholar
  14. 14.
    Mittal N, Joshi R, Hota D, Chakrabarti A (2009) Evaluation of antihyperalgesic effect of curcumin on formalin-induced orofacial pain in rat. Phytother Res 23:507–512CrossRefPubMedGoogle Scholar
  15. 15.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358CrossRefPubMedGoogle Scholar
  16. 16.
    Sharma R, Vinayak M (2011) α-Tocopherol attenuates NF-κB activation and pro-inflammatory cytokine secretion in cancer-bearing mice. Biosci Rep 31:421–428CrossRefPubMedGoogle Scholar
  17. 17.
    Aebi H (1974) catalase. In: Bergmeyer HU (ed) Methods in enzymatic analysis, 2nd edn. Academic Press, New York, pp 673–678CrossRefGoogle Scholar
  18. 18.
    Winterbourne CC, Hawkins RE, Brian M, Carrell RW (1975) The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85:337–341Google Scholar
  19. 19.
    Pagalia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169Google Scholar
  20. 20.
    Ho YS, Magnenat JL, Bronson RT, Cao J, Gargano M, Sugawara M et al (1997) Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J Biol Chem 272(26):16644–16651CrossRefPubMedGoogle Scholar
  21. 21.
    Horn HD (1965) Glutathione reductase. In: Bergmeyer H (ed) Methods of enzyme analysis. Academic Press, New York, pp 875–879CrossRefGoogle Scholar
  22. 22.
    Ren K, Dubner R (1999) Inflammatory models of pain and hyperalgesia. ILAR J 40(3):111–118CrossRefPubMedGoogle Scholar
  23. 23.
    Billiau A, Matthys P (2001) Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol 70:849–860PubMedGoogle Scholar
  24. 24.
    Salvemini D, Little JW, Doyle T, Neumann WL (2011) Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med 51(951–966):4Google Scholar
  25. 25.
    Bowie A, O’Neill LA (2000) Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59(1):13–23CrossRefPubMedGoogle Scholar
  26. 26.
    Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210CrossRefPubMedGoogle Scholar
  27. 27.
    Varija D, Kumar KP, Reddy KP, Reddy VK (2008) Prolonged constriction of sciatic nerve affecting oxidative stressors and antioxidant enzymes in rat. Indian J Med Res 129(587–592):7Google Scholar
  28. 28.
    Guedes RP, Bosco LD, Teixeira CM, Araújo ASR, Llesuy S, Belló-Klein A et al (2006) Neuropathic pain modifies antioxidant activity in rat spinal cord. Neurochem Res 31:603–609CrossRefPubMedGoogle Scholar
  29. 29.
    Stefanson AL, Bakovic M (2014) Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients 6:3777–3801CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R et al (2003) Curcumin activates the haemoxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 371:887–895CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Singh S, Aggarwal BB (1995) Activation of transcription factor NF-kB is suppressed by curcumin (diferulolylmethane). J Biol Chem 270(20):24995–25000CrossRefPubMedGoogle Scholar
  32. 32.
    Viggiano A, Monda M, Viggiano A, Viggiano D, Viggiano E, Chiefari M et al (2005) Trigeminal pain transmission requires reactive oxygen species production. Brain Res 1050:72–78CrossRefPubMedGoogle Scholar
  33. 33.
    Chen Y, Boettger MK, Reif A, Schmitt A, Üçeyler N, Sommer C (2010) Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. Mol Pain 6:13CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Matata BM, Galinanes M (2002) Peroxynitrite is an essential component of cytokine production mechanism in human monocytes through modulation of nuclear factor-kappa B DNA binding activity. J Biol Chem 277:2330–2335CrossRefPubMedGoogle Scholar
  35. 35.
    Das L, Vinayak M (2014) Curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 in lymphoma bearing mice. Int Immunopharmacol 20:141–147CrossRefPubMedGoogle Scholar
  36. 36.
    Sancho P, Martín-Sanz P, Fabregat I (2011) Reciprocal regulation of NADPH oxidases and the cyclooxygenase-2 pathway. Free Radic Biol Med 51:1789–1798CrossRefPubMedGoogle Scholar
  37. 37.
    Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455CrossRefPubMedGoogle Scholar
  38. 38.
    Rittner HL, Machelska H, Stein C (2005) Leuckocyte in the regulation of pain and analgesia. J Leukoc Biol 78:1215–1222CrossRefPubMedGoogle Scholar
  39. 39.
    Hensellek S, Brell P, Schaible HG, Bräuer R, von Bancheta GS (2007) The cytokine TNFα increases the proportion of DRG neurons expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci 36:381–391CrossRefPubMedGoogle Scholar
  40. 40.
    Ji RR, Befort K, Brenner GJ, Woolf CJ (2002) ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 22(2):478–485PubMedGoogle Scholar
  41. 41.
    Puntambekar P, Mukharjea D, Jajoo S, Ramkumar V (2005) Essential role of Rac1/NADPH oxidase in nerve growth factor induction of TRPV1 expression. J Neurochem 95(6):1689–1703CrossRefPubMedGoogle Scholar
  42. 42.
    Cunha FQ, Ferrreria SH (2003) Peripheral hyperalgesic cytokines. Adv Exp Med Biol 521:22–39PubMedGoogle Scholar
  43. 43.
    Colston JT, Chandrasekar B, Freeman GL (2002) A novel peroxide-induced calcium transient regulates interleukin-6 expression in cardiac-derived fibroblasts. J Biol Chem 277:23477–23483CrossRefPubMedGoogle Scholar
  44. 44.
    Sredni-Kenigsbuch D, Kambayashi T, Strassmann G (2000) Neutrophils augment the release of TNF alpha from LPS-stimulated macrophages via hydrogen peroxide. Immunol Lett 71:97–102CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study in ZoologyBanaras Hindu UniversityVaranasiIndia

Personalised recommendations