Skip to main content

Advertisement

SpringerLink
Log in

Pathophysiology of Medication-overuse Headache: Implications from Animal Studies

  • Chronic Daily Headache (SJ Wang, Section Editor)
  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Recent animal experiments have shown that chronic medication exposure profoundly affects the function of several areas in the nervous system related to headache pathogenesis. These changes include upregulation of calcitonin gene–related peptide, substance P, and nitric oxide synthase in trigeminal ganglia; expansion of receptive field and decreased nociceptive threshold of central trigeminal neurons; decrease in diffuse noxious inhibitory control; and increased susceptibility to develop cortical spreading depression (CSD). These changes indicate an increase in excitability of cortical and trigeminal neurons. The neuronal hyperexcitability may be the result of derangement of a central, possibly serotonin (5-HT)-dependent, modulating control system. Experiments with animals with low 5-HT showed that the processes of CSD and trigeminal nociception are enhanced in this condition. Derangement in the central 5-HT–dependent modulating system as a result of chronic medication use may underlie the chronification of headache as observed in patients with medication-overuse headache.

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

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9–160.

    Google Scholar 

  2. Colas R, Munoz P, Temprano R, et al. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338–42.

    PubMed  CAS  Google Scholar 

  3. Meskunas CA, Tepper SJ, Rapoport AM, Sheftell FD, Bigal ME. Medications associated with probable medication overuse headache reported in a tertiary care headache center over a 15-year period. Headache. 2006;46:766–72.

    Article  PubMed  Google Scholar 

  4. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59:652–61.

    Article  PubMed  CAS  Google Scholar 

  5. Bogdanov VB, Multon S, Chauvel V, et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol Dis. 2011;41:430–5.

    Article  PubMed  CAS  Google Scholar 

  6. Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A. Serotonin depletion, cortical spreading depression and trigeminal nociception. Headache. 2006;46:34–9.

    Article  PubMed  Google Scholar 

  7. Brennan KC, Romero Reyes MR, Lòpez Valdés HE, Arnold AP, Charles AC. Reduced threshold for cortical spreading depression in female mice. Ann Neurol. 2007;61:603–6.

    Article  PubMed  Google Scholar 

  8. •• Supornsilpchai W, le Grand SM, Srikiatkhachorn A. Cortical hyperexcitability and mechanism of medication-overuse headache. Cephalalgia 2010;30:1101–1109. This study demonstrates the increase in frequency of CSD in rats chronically treated with acetaminophen.

    Article  PubMed  Google Scholar 

  9. Grazzi L, Chiapparini L, Ferraro S, et al. Chronic migraine with medication overuse pre–post withdrawal of symptomatic medication: clinical results and fMRI correlations. Headache. 2010;50:998–1004.

    Article  PubMed  Google Scholar 

  10. •• De Felice M, Ossipov MH, Wang R, et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol 2010;67:325–37. This article demonstrates increased algogenic peptide expression in trigeminal ganglia and latent sensitization in rats with chronic triptan exposure.

    PubMed  Google Scholar 

  11. Belanger S, Ma W, Chabot JG, Quirion R. Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates. Neuroscience. 2002;115:441–53.

    Article  PubMed  CAS  Google Scholar 

  12. Ma W, Zheng WH, Kar S, Quirion R. Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. Neuroscience. 2000;99:529–39.

    Article  PubMed  CAS  Google Scholar 

  13. Gardell LR, Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci. 2002;22:6747–55.

    PubMed  CAS  Google Scholar 

  14. •• De Felice M, Ossipov MH, Wang R, et al. Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 2010;133:2475–2488. This article demonstrates the effect of chronic triptan exposure on expression of nitric oxide synthase in trigeminal ganglia.

    Article  PubMed  Google Scholar 

  15. •• Okada-Ogawa A, Porreca F, Meng ID. Sustained morphine-induced sensitization and loss of diffuse noxious inhibitory controls in dura-sensitive medullary dorsal horn neurons. J Neuroscience 2009; 29:15828 –15835. This article demonstrates the impairment of the diffuse noxious inhibitory controls in dura-sensitive medullary dorsal horn neurons after prolonged use of morphine.

    Article  CAS  Google Scholar 

  16. Srikiatkhachorn A, Tarasub N, Govitrapong P. Effect of chronic analgesic exposure on the central serotonin system. A possible mechanism of analgesic abuse headache. Headache. 2000;40:343–50.

    Article  PubMed  CAS  Google Scholar 

  17. •• Supornsilpchai W, le Grand SM, Srikiatkhachorn A. Involvement of pro-nociceptive 5-HT2A receptor in the pathogenesis of medication-overuse headache. Headache 2010;50:185–197. This article demonstrates the upregulation of pronociceptive 5-HT 2A receptor in rats chronically treated with acetaminophen. It also shows that antagonist to this receptor can attenuate the susceptibility to CSD in this animals.

    Article  PubMed  Google Scholar 

  18. Reuter U, Salomone S, Ickenstein GW, Waeber C. Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT receptor expression and function in rats. Cephalalgia. 2004;24:398–407.

    Article  PubMed  CAS  Google Scholar 

  19. Dobson CF, Tohyama Y, Diksic M, Hamel E. Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. Cephalalgia. 2004;24:2–11.

    Article  PubMed  CAS  Google Scholar 

  20. Drummond PD. Tryptophan depletion increases nausea, headache and photophobia in migraine sufferers. Cephalalgia. 2006;26:1225–33.

    Article  PubMed  CAS  Google Scholar 

  21. Srikiatkhachorn A, Anthony M. Platelet serotonin in patients with analgesic-induced headache. Cephalalgia. 1996;16:423–6.

    Article  PubMed  CAS  Google Scholar 

  22. le Grand SM, Supornsilpchai W, Saengjaroentham C, Srikiatkhachorn A. Serotonin depletion leads to cortical hyperexcitability and trigeminal nociceptive facilitation via the nitric oxide pathway. Headache. 2011;51:1152–60.

    Article  PubMed  Google Scholar 

  23. Srikiatkhachorn A, Suwattanasophon C, Ruangpattanatawee A, Phansuwan-Pujito P. 5-HT2A receptor activation and nitric oxide synthesis: a possible mechanism determining migraine attacks. Headache. 2002;42:566–74.

    Article  PubMed  Google Scholar 

  24. Maneepak M, le Grand S, Srikiatkhachorn A. Serotonin depletion increases nociception-evoked trigeminal NMDA receptor phosphorylation. Headache. 2009;49:375–82.

    Article  PubMed  Google Scholar 

  25. Le Grand S, Saengjaroentham C, Supronsilpchai W, Srikiatkhachorn A. The increase in the calcitonin gene-related peptide immunoreactivity following the CSD activation in the serotonin depleted state. J Headache Pain. 2010;11 Suppl 1:S136–137.

    Google Scholar 

  26. Perrotta A, Serrao M, Sandrini G, Burstein R, Sances G, Rossi P, Bartolo M, Pierelli F, Nappi G. Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control. Cephalalgia. 2010;30:272–84.

    PubMed  CAS  Google Scholar 

  27. Fusco BM, Colantoni O, Giacovazzo M. Alteration of central excitation circuits in chronic headache and analgesic misuse. Headache. 1997;35:486–91.

    Article  Google Scholar 

  28. Schnider P, Maly J, Grunberger J, et al. Improvement of decreased critical flicker frequency (CFF) in headache patients with drug abuse after successful withdrawal. Headache. 1995;35:269–72.

    Article  PubMed  CAS  Google Scholar 

  29. Evers S, Schmidt F, Bauer B, et al. The impact of ergotamine-induced headache and ergotamine withdrawal on information processing. Psychopharmacology. 1999;142:61–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Neuroscience of Headache Research Unit, the Thailand Research Fund (RTA5180004 and MRG5280061) and the Ratchadapiseksompotch Fund from the Faculty of Medicine, Chulalongkorn University.

Disclosures

No potential conflicts of interest relevant to this article were reported

Author information

Authors and Affiliations

  1. Neuroscience Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Patumwan, Bangkok, Thailand, 10330

    Saknan Bongsebandhu-phubhakdi & Anan Srikiatkhachorn

Authors
  1. Saknan Bongsebandhu-phubhakdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anan Srikiatkhachorn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anan Srikiatkhachorn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bongsebandhu-phubhakdi, S., Srikiatkhachorn, A. Pathophysiology of Medication-overuse Headache: Implications from Animal Studies. Curr Pain Headache Rep 16, 110–115 (2012). https://doi.org/10.1007/s11916-011-0234-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-011-0234-y

Keywords

Search

Navigation