Current Pain and Headache Reports

, Volume 11, Issue 2, pp 98–103 | Cite as

The relationship between cytokines and pain/depression: A review and current status

  • Thomas B. StrouseEmail author


Cytokines are small protein molecules secreted in response to immune stimuli. Recent research has outlined important roles for proinflammatory cytokines in the cascade of normal physiologic responses to environmental stresses, encompassing so-called sickness behavior that is thought to be an adaptive response to infection and other illnesses. Cytokines are involved in signaling that activates central nervous system glial cells. This activation is part of a poorly understood interaction between immune challenge or injury and host that can lead to the development or facilitation of persistent mood symptoms or pathologic pain. This article reviews evidence that may enhance our understanding of how pathologic symptoms, such as mood disorders and neuropathic pain, may emerge from proinflammatory cytokine activation. Possible conceptualizations of these illnesses and potential treatment implications are explored.


Neuropathic Pain Paroxetine DHEA Duloxetine Glial Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Horst Ibelgauft’s COPE with Cytokines. Available at Accessed October 10, 2006.
  2. 2.
    Ransohoff RM, Benveniste EN: Cytokines and the CNS. New York: Taylor & Francis; 2006.Google Scholar
  3. 3.
    Smith DD: Optimization of cellular ELISA for assay of surface antigens on human synoviocytes. Biotechniques 1997, 22:952–957.PubMedGoogle Scholar
  4. 4.
    Dinarello CA. Proinflammatory cytokines. Chest 2000, 118:503–508.PubMedCrossRefGoogle Scholar
  5. 5.
    Hart BL: Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988, 12:123–137.PubMedCrossRefGoogle Scholar
  6. 6.
    Maier SF, Watkins LR: Cytokine for psychologists: implications for bi-directional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Rev 1998, 105:83–107.CrossRefGoogle Scholar
  7. 7.
    Kent S, Bluthe RM, Kelley KW, Dantzer R: Sickness behavior as a new target for drug development. Trends Pharmacol Sci 1992, 13:24–28.PubMedCrossRefGoogle Scholar
  8. 8.
    Parnet P, Kelley KW, Bluthe RM: Expression and regulation of IL-1 receptors in the brain. Role in cytokine-induced sickness behavior. J Neuroimmunol 2002, 125:5–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Gutierrez EG, Banks WA, Kastin AJ: Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 1993, 47:169–176.PubMedCrossRefGoogle Scholar
  10. 10.
    Gutierrez EG, Banks WA, Kastin AJ: Blood-borne interleukin-1 receptor antagonist crosses the blood brain barrier. J Neuroimmunol 1994, 55:153–160.PubMedCrossRefGoogle Scholar
  11. 11.
    Illman J, Corringham R, Robinson D, et al.: Are inflammatory cytokines the common link between cancer-associated cachexia and depression? J Support Oncol 2005, 3:37–50.PubMedGoogle Scholar
  12. 12.
    Leonard BE: The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2001, 25:767–780.PubMedCrossRefGoogle Scholar
  13. 13.
    Ramamoorthy S, Ramamorthy JD, Pradad P, et al.: Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res Commun 1995, 216:560–567.PubMedCrossRefGoogle Scholar
  14. 14.
    Wilson CR, Finch CE, Cohen HJ: Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002, 50:2041–2056.PubMedCrossRefGoogle Scholar
  15. 15.
    Penninx BW, Kritchevsky SB, Yaffe K, et al.: Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition study. Biol Psychiatry 2003, 54:566–572.PubMedCrossRefGoogle Scholar
  16. 16.
    Capuron L, Ravaud A, Neveu PJ, et al.: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002, 7:468–473.PubMedCrossRefGoogle Scholar
  17. 17.
    Delgado PL, Price LH, Miller HL, et al.: Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Genet Psychol 2004, 51:865–874.Google Scholar
  18. 18.
    Musselman DL, Lawson DH, Gumnick JF et al.: Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001, 344:961–966.PubMedCrossRefGoogle Scholar
  19. 19.
    Capuron L, Ravaud A, Gualde N, et al.: Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2 based therapy. Psychoneuroendocrinology 2001, 26:797–808.PubMedCrossRefGoogle Scholar
  20. 20.
    Capuron L, Ravaud A, Neveu PJ, et al.: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002, 7:468–473.PubMedCrossRefGoogle Scholar
  21. 21.
    Demetrashvilli M, Raison CL, Miller AH: Depression in at-risk populations. Cent Nerv Syst News 2002, 4:9–12.Google Scholar
  22. 22.
    Cleeland CS, Bennett GJ, Dantzer R, et al.: Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer 2003, 97:2919–2925.PubMedCrossRefGoogle Scholar
  23. 23.
    Trikha M, Corringham R, Klein B, et al.: Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003, 9:4653–4665.PubMedGoogle Scholar
  24. 24.
    Musselman DL, Miller AH, Porter MR, et al.: Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychol 2001, 158:1252–1257.CrossRefGoogle Scholar
  25. 25.
    Pace TWW, Miletzko TC, Alagbe O, et al.: Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychol 2006, 163:1630–1633.CrossRefGoogle Scholar
  26. 26.
    Castanon N, Leonard BE, Neveu PJ, Yirmiya R: Effects of antidepressants on cytokine production and actions. Brain Behav Immun 2002, 16:569–574.PubMedCrossRefGoogle Scholar
  27. 27.
    Pollak Y, Yirmiya R: Cytokine-induced changes in mood and behavior: implications for “depression due to a general medical condition,” immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol 2002, 5:389–399.PubMedCrossRefGoogle Scholar
  28. 28.
    Leonard BE: The immune system, depression, and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2001, 25:767–780.PubMedCrossRefGoogle Scholar
  29. 29.
    Wieseler-Frank J, Maier SF, Watkins L: Central proinflammatory cytokines and pain enhancement. Neurosignals 2005, 14:166–174.PubMedCrossRefGoogle Scholar
  30. 30.
    Watkins LR, Maier SF: Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 2005, 257:139–155.PubMedCrossRefGoogle Scholar
  31. 31.
    Myers RR, Wagner R, Sorkin LS: Hyperalgesic actions of cytokines on peripheral nerves. In Cytokines and Pain. Edited by Watkins LR, Maier SF. Basel, Switzerland: Birkhause; 1999:133–158.Google Scholar
  32. 32.
    Twining CM, Sloane EM, Milligan ED, et al.: Peri-sciatic proinflammatory cytokines, reactive oxygen species, and complement induce mirror-image neuropathic pain in rats. Pain 2004, 110:299–309.PubMedCrossRefGoogle Scholar
  33. 33.
    Lindenlaub T, Sommer C: Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol 2003, 105:593–602.PubMedGoogle Scholar
  34. 34.
    Kagan BL, Baldwin RL, Munoz D, et al.: Formation of ionpermeable channels by tumor necrosis factor-alpha. Science 1992, 255:1427–1430.PubMedCrossRefGoogle Scholar
  35. 35.
    Qiu Z, Sweeney DD, Netzeband JF, et al.: Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J Neurosci 1998, 18:10445–10456.PubMedGoogle Scholar
  36. 36.
    Sweitzer SM, Colburn RW, Rutkowski M, et al.: Acute peripheral inflammation induces moderate glial activation and spinal IL-1 beta expression that correlates with pain behavior in the rat. Brain Res 1999, 829:209–221.PubMedCrossRefGoogle Scholar
  37. 37.
    Sweitzer SM, Martin D, DeLeo JA: Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 2001, 103:529–539.PubMedCrossRefGoogle Scholar
  38. 38.
    Raison CL, Nemeroff CB: Cancer and depression: prevalence, diagnosis, and treatment. Home Health Consult 2000, 7:34–41.Google Scholar
  39. 39.
    Baldessarini RJ, Tondo L, Davis P, et al.: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006, 8:625–639.PubMedCrossRefGoogle Scholar
  40. 40.
    Frank E, Thase M: Natural history and preventative treatment of recurrent mood disorders. Annu Rev Med 1999, 50:453–468.PubMedCrossRefGoogle Scholar
  41. 41.
    Xie W, Strong J, Meij J: Neuropathic pain: early spontaneous afferent activity is the trigger. Pain 2005, 116:243–256.PubMedCrossRefGoogle Scholar
  42. 42.
    Foley KM: Opioids and chronic neuropathic pain. N Engl J Med 2003, 348:1279–1281.PubMedCrossRefGoogle Scholar
  43. 43.
    Lloyd AJ, Ferrier IN, Barber R, et al.: Hippocampal volume change in depression: late-and early-onset illness compared. Br J Psychol 2004, 184:488–495.CrossRefGoogle Scholar
  44. 44.
    Apkarian AV, Sosa Y, Sonty S, et al.: Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. Neuroscience 2004, 24:10410–10415.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.UCLA Department of Psychiatry and Biobehavioral Sciences, Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer InstituteUCLA and Cedars-Sinai Medical CentersLos AngelesUSA

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