Skip to main content

Migraine pain, meningeal inflammation, and mast cells

Abstract

Migraine pain has been attributed to an episode of local sterile meningeal inflammation and the subsequent activation of trigeminal primary afferent nociceptive neurons that supply the intracranial meninges and their related large blood vessels. However, the origin of this inflammatory insult and the endogenous factors that contribute to the activation of meningeal nociceptors remain largely speculative. A particular class of inflammatory cells residing within the intracranial milieu, known as meningeal mast cells, was suggested to play a role in migraine pathophysiology more than five decades ago, but until recently the exact nature of their involvement remained largely unexplored. This review examines the evidence linking meningeal mast cells to migraine and highlights current experimental data implicating these immune cells as potent modulators of meningeal nociceptors’ activity and the genesis of migraine pain.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. 1.

    Lipton RB, Bigal ME, Diamond M, et al.: Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007, 68:343–349.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Burstein R: Deconstructing migraine headache into peripheral and central sensitization. Pain 2001, 89:107–110.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Pietrobon D, Striessnig J: Neurobiology of migraine. Nat Rev Neurosci 2003, 4:386–398.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Waeber C, Moskowitz MA: Migraine as an inflammatory disorder. Neurology 2005, 64(Suppl 2):S9–S15.

    PubMed  Google Scholar 

  5. 5.

    Goadsby PJ, Edvinsson L: The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993, 33:48–56.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Sarchielli P, Alberti A, Baldi A, et al.: Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 2006, 46:200–207.

    PubMed  Article  Google Scholar 

  7. 7.

    Wenzel RG, Sarvis CA, Krause ML: Over-the-counter drugs for acute migraine attacks: literature review and recommendations. Pharmacotherapy 2003, 23:494–505.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Moskowitz MA: Pathophysiology of headache: past and present. Headache 2007, 47(Suppl 1):S58–S63.

    PubMed  Article  Google Scholar 

  9. 9.

    Lauritzen M: Cortical spreading depression in migraine. Cephalalgia 2001, 21:757–760.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Bolay H, Reuter U, Dunn AK, et al.: Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002, 8:136–142.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Colonna DM, Meng W, Deal DD, Busija DW: Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits. Am J Physiol 1994, 266(3 Pt 2):H1095–H1102.

    PubMed  CAS  Google Scholar 

  12. 12.

    Strassman AM, Raymond SA, Burstein R: Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996, 384:560–564.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Theoharides TC, Kalogeromitros D: The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci 2006, 1088:78–99.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Mekori YA, Metcalfe DD: Mast cells in innate immunity. Immunol Rev 2000, 173:131–140.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Dimlich RV, Keller JT, Strauss TA, Fritts MJ: Linear arrays of homogeneous mast cells in the dura mater of the rat. J Neurocytol 1991, 20:485–503.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Strassman AM, Weissner W, Williams M, et al.: Axon diameters and intradural trajectories of the dural innervation in the rat. J Comp Neurol 2004, 473:364–376.

    PubMed  Article  Google Scholar 

  17. 17.

    Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, et al.: Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res 1999, 849:1–15.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Sicuteri F: Mast cell and their active substances: their role in the pathogenesis of migraine. Headache 1963, 3:86.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Monro J, Carini C, Brostoff J: Migraine is a food-allergic disease. Lancet 1984, 2:719–721.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Heatley RV, Denburg JA, Bayer N, Bienenstock J: Increased plasma histamine levels in migraine patients. Clin Allergy 1982, 12:145–149.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Lassen LH, Thomsen LL, Olesen J: Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine. Neuroreport 1995, 6:1475–1479.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Rossi P, Fiermonte G, Pierelli F: Cinnarizine in migraine prophylaxis: efficacy, tolerability and predictive factors for therapeutic responsiveness. An open-label pilot trial. Funct Neurol 2003, 18:155–159.

    PubMed  Google Scholar 

  23. 23.

    Lewis DW, Diamond S, Scott D, Jones V: Prophylactic treatment of pediatric migraine. Headache 2004, 44:230–237.

    PubMed  Article  Google Scholar 

  24. 24.

    Togha M, Ashrafian H, Tajik P: Open-label trial of cinnarizine in migraine prophylaxis. Headache 2006, 46:498–502.

    PubMed  Article  Google Scholar 

  25. 25.

    Sheftell F, Rapoport A, Weeks R, et al.: Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers. Headache 2000, 40:158–163.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Hasselblatt M, Kohler J, Volles E, Ehrenreich H: Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine. Neuroreport 1999, 10:423–425.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Low NC, Merikangas KR: The comorbidity of migraine. CNS Spectr 2003, 8:433–434, 437–444.

    PubMed  Google Scholar 

  28. 28.

    Ottosson A, Edvinsson L: Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia 1997, 17:166–174.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Seebeck J, Kruse ML, Schmidt-Choudhury A, Schmidt WE: Pituitary adenylate cyclase activating polypeptide induces degranulation of rat peritoneal mast cells via high-affinity PACAP receptor-independent activation of G proteins. Ann N Y Acad Sci 1998, 865:141–146.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Schwenger N, Dux M, de Col R, et al.: Interaction of calcitonin gene-related peptide, nitric oxide and histamine release in neurogenic blood flow and afferent activation in the rat cranial dura mater. Cephalalgia 2007, 27:481–491.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Lassen LH, Haderslev PA, Jacobsen VB, et al.: CGRP may play a causative role in migraine. Cephalalgia 2002, 22:54–61.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Schytz HW, Birk S, Wienecke T, et al.: PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009, 132(Pt 1):16–25.

    PubMed  Google Scholar 

  33. 33.

    Lennerz JK, Ruhle V, Ceppa EP, et al.: Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol 2008, 507:1277–1299.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Levy D, Burstein R, Strassman AM: Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 2005, 58:698–705.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Theoharides TC, Spanos C, Pang X, et al.: Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. Endocrinology 1995, 136:5745–5750.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Reuter U, Bolay H, Jansen-Olesen I, et al.: Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001, 124 (Pt 12):2490–2502.

    Article  Google Scholar 

  37. 37.

    Burstein R, Jakubowski M: Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol 2005, 493:9–14.

    PubMed  Article  Google Scholar 

  38. 38.

    Delepine L, Aubineau P: Plasma protein extravasation induced in the rat dura mater by stimulation of the parasympathetic sphenopalatine ganglion. Exp Neurol 1997, 147:389–400.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Yu S, Kollarik M, Ouyang A, et al.: Mast cell-mediated long-lasting increases in excitability of vagal c-fibers in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 2007, 293:G850–G856.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Coldwell JR, Phillis BD, Sutherland K, et al.: Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery. J Physiol 2007, 579(Pt 1):203–213.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Barbara G, Wang B, Stanghellini V, et al.: Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007, 132:26–37.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Levy D, Burstein R, Kainz V, et al.: Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 2007, 130:166–176.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Zhang X, Strassman AM, Burstein R, Levy D: Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther 2007, 322:806–812.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Zhang XC, Levy D: Modulation of meningeal nociceptors mechanosensitivity by peripheral proteinase-activated receptor-2: the role of mast cells. Cephalalgia 2008, 28:276–284.

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dan Levy.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Levy, D. Migraine pain, meningeal inflammation, and mast cells. Current Science Inc 13, 237–240 (2009). https://doi.org/10.1007/s11916-009-0040-y

Download citation

Keywords

  • Migraine
  • Mast Cell
  • Migraine Attack
  • Interstitial Cystitis
  • Pituitary Adenylate Cyclase Activate Polypeptide