Journal of Neurology

, Volume 238, Supplement 1, pp S38–S44 | Cite as

5-Hydroxytryptamine and the pathophysiology of migraine

  • P. P. A. Humphrey
Migraine Therapy And 5-HT Receptor Activity

Summary

5-Hydroxytryptamine (5-HT; serotonin) has long been implicated in the aetiology of migraine but the evidence remains circumstantial and certainly not definitive. Numerous papers have reviewed the background which is briefly outlined here. Although the continued belief in the primary involvement of 5-HT in the genesis of a migraine attack has recently been questioned, many antimigraine drugs undeniably interact potently with 5-HT receptors. It can be argued, however, that their modest clinical benefit results from their pharmacological effects, be they mediated through 5-HT receptors or otherwise, independently of any pathophysiological involvement of endogenous 5-HT. Nevertheless, there seems convincing evidence that central release of 5-HT by various drug mechanisms causes migraine-like headache in migraineurs. It remains to be seen whether these drugs mimic the pathological event initiating the spontaneous migraine attack. Regardless of these considerations, the focus of research on 5-HT and migraine has proved to be enormously profitable over several decades, culminating recently in the identification of a novel, potentially important, antimigraine drug for the treatment of the acute attack. This drug, sumatriptan, is a selective cranial vasoconstrictor which mediates this effect by specifically activating a particular 5-HT1 receptor subtype. Undoubtedly a precise understanding of its clinical mechanism of action, which is currently being studied by a number of groups, will lead to a better understanding of the pathogenesis of migraine. Perhaps this in turn will help in finally determining whether migraine is a vascular disease and whether or not a disturbance of 5-HT is just epiphenomenal or is truly the primary initiating pathological event.

Key words

5-Hydroxytryptamine Serotonin Antimigraine drugs Sumatriptan Pathophysiology 

References

  1. 1.
    Angus JA, Van Nueten JM (1989) Pathophysiology of 5-hydroxytryptamine: an overview. In: Mylecharane EJ, Angus JA, de la Lande IS, Humphrey PPA (eds) Serotonin actions, receptors, pathophysiology. Macmillan Press, Basingstoke, pp 274–279Google Scholar
  2. 2.
    Anthony M, Hinterberger H, Lance JW (1967) Plasma serotonin in migraine and stress. Arch Neurol 16:544–552Google Scholar
  3. 3.
    Anthony M, Hinterberger H, Lance JW (1967) The possible relationship of serotonin to the migraine syndrome. Res Clin Study Headache 2:29–59Google Scholar
  4. 4.
    Badia A, Maron A, Cuffi L, Vila E (1988) Effect of ergotamine on cardiovascular catecholamine receptors in the pithed rat. Gen Pharmacol 19:475–481Google Scholar
  5. 5.
    Bagdy G, Szemeredi K, Zukowska-Grojec Z, Hill J, Murphy DL (1987)m-Chlorophenylpiperazine increases blood pressure and heart rate in pithed and conscious rats. Life Sci 41:775–782Google Scholar
  6. 6.
    Blau JN, Dexter SL (1981) The site of pain origin during migraine attacks. Cephalalgia 1:143–147Google Scholar
  7. 7.
    Blau JN, Solomon F (1985) Migraine and intracranial swelling: an experiment of nature. Lancet II:718Google Scholar
  8. 8.
    Bouchard JM, Delaunay J, Delisle JP, Grasset N, Mermberg PF, Molczadzki M, Pagot R, Richou H, Robert G, Ropert R, Schuller E, Verdeau-Pailles J, Zarifian E, Hopfner-Petersen HE (1987) Citalopram versus maprotiline: a controlled, clinical, multicentre trial in depressed patients. Acta Psychiatr Scand 76:583–592Google Scholar
  9. 9.
    Brazil P, Friedman AP (1956) Craniovascular studies in headache: a report and analysis of pulse volume trainings. Neurology 6:96–102Google Scholar
  10. 10.
    Brewerton TD, Murphy DL, Mueller EA, Jimerson DC (1988) Induction of migraine-like headaches by the serotonin agonistm-chlorophenylpiperazine. Clin Pharmacol Ther 43:605–609Google Scholar
  11. 11.
    Buzzi MG, Moskowitz MA (1990) The anti-migraine drug sumatriptan (GR43175) selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 99:202–206Google Scholar
  12. 12.
    Carroll JD, Hilton BP (1974) The effects of reserpine injection on methysergide treated control and migrainous subjects. Headache 14:149–156Google Scholar
  13. 13.
    Cohen ML, Fuller RW (1983) Antagonism of vascular serotonin receptors bym-chlorophenylpiperazine andm-trifluoromethylphenylpiperazine. Life Sci 32:711–718Google Scholar
  14. 14.
    Curran DA, Hinterberger H, Lance JW (1965) Total plasma serotonin, 5-hydroxyindoleacetic acid andp-hydroxy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain 88:997–1007Google Scholar
  15. 15.
    Curran DA, Lance JW (1964) Clinical trial of methysergide and other preparations in the management of migraine. J Neurol Neurosurg Psychiatry 27:463–469Google Scholar
  16. 16.
    Curran HV, Lader M (1986) The psychopharmacological effects of repeated doses of fluvoxamine, mianserin and placebo in healthy human subjects. Eur J Clin Pharmacol 29:601–607Google Scholar
  17. 17.
    Curzon G, Theaker P, Phillips B (1966) Excretion of 5-hydroxyindolyl acetic acid (5HIAA) in migraine. J Neurol Neurosurg Psychiatry 29:85–90Google Scholar
  18. 18.
    Del Bene E, Anselmi B, Del Bianco PL, Fanciullacci M, Galli P, Salmon S, Sicuteri F (1977) Fenfluramine headache: a biochemical and monoamine receptorial human study. In: Sicuteri F (ed) Headache: new vistas. Biomedical Press, Florence, pp 101–109Google Scholar
  19. 19.
    Drummond PD, Lance JW (1983) Extracranial vascular changes and the source of pain in migraine headache. Ann Neurol 13:32–37Google Scholar
  20. 20.
    Dvilansky A, Rishpon S, Nathan I, Zolotow Z, Korczyn AD (1976) Release of platelet 5-hydroxytryptamine by plasma taken from patients during and between migraine attacks. Pain 2:315–318Google Scholar
  21. 21.
    Edmeads J (1991) What is migraine? Controversy and stalemate in migraine pathophysiology. J Neurol 238 (suppl 1):S2-S5Google Scholar
  22. 22.
    Feniuk W, Humphrey PPA, Perren MJ: GR43175 does not share the complex pharmacology of the ergots. Cephalalgia 9 (suppl 9):35–39Google Scholar
  23. 23.
    Feniuk W, Humphrey PPA, Perren MJ, Connor HF, Whalley ET (1991): Rationale for the use of 5-HT1-like agonists in the treatment of migraine. J Neurol 238 (suppl 1):S57-S61Google Scholar
  24. 24.
    Ferrari MD (1991) 5-HT3 receptor antagonists and migraine therapy. J Neurol 238 (suppl 1):S53-S56Google Scholar
  25. 25.
    Ferrari MD, Fröhlich M, Odink J, Tapparelli C, Portielje JEA, Bruyn GW (1987) Methionine-enkephalin and serotonin in migraine and tension headache. In: Rose FC (ed) Advances in headache research. John Libbey, London, pp 227–234Google Scholar
  26. 26.
    Ferrari MD, Odink J (1989) Urinary excretion of biogenic amines camines in migraine and tension headache. In: Rose FC (ed) New advances in headache research. Smith-Gordon, London, pp 85–88Google Scholar
  27. 27.
    Ferrari MD, Odink J, Tapparelli C, Van Kempen GMJ, Pennings EJM, Bruyn GW (1989) Serotonin metabolism in migraine. Neurology 39:1239–1242Google Scholar
  28. 28.
    Fozard JR (1975) The animal pharmacology of drugs used in the treatment of migraine. J Pharm Pharmacol 27:297–321Google Scholar
  29. 29.
    Fozard JR (1982) Serotonin, migraine and platelets. Prog Pharmacol 4:136–146Google Scholar
  30. 30.
    Fozard JR (1990) 5-HT in migraine: evidence from 5-HT receptor antagonists for a neuronal aetiology. In: Sandler M, Collins G (eds) Migraine — a spectrum of ideas. Oxford University Press, Oxford, pp 128–146Google Scholar
  31. 31.
    Fozard JR, Gray JA (1989) 5-HT1C receptor activation: a key step in the initiation of migraine? Trends in Pharmacol Sci 10:307–309Google Scholar
  32. 32.
    Friberg (1991) Cerebral blood flow changes in migraine: methods, observations and hypotheses. J Neurol 238 (suppl 1):S12-S17Google Scholar
  33. 33.
    Genefke IK, Dalsgaard-Nielsen T, Bryndum B, Fog-Moller F, Jensen JAP (1975) Concentration of serotonin in blood platelets: effect of reserpine in migraineurs. Headache 15:136–138Google Scholar
  34. 34.
    Goltman AM (1935) Mechanism of migraine. J Allergy 7:351–355Google Scholar
  35. 35.
    Gomersall JD, Stuart A (1973) Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry 36:684–690Google Scholar
  36. 36.
    Graham JR, Wolff HG (1938) Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 39:737–763Google Scholar
  37. 37.
    Hachinski V, Norris JW, Edmeads J, Cooper PW (1978) Ergotamine and cerebral blood flow. Stroke 9:594–596Google Scholar
  38. 38.
    Hamel E, Robert J-P, Young AR, MacKenzie ET (1989) Pharmacological properties of the receptor(s) involved in the 5-hydroxytryptamine-induced contraction of the feline middle cerebral artery. J Pharmacol Exp Ther 249:879–889Google Scholar
  39. 39.
    Hanko J, Hardebo JE, Kahstrom J, Owman C, Sundler F (1985) Calcitonin gene-related peptide is present in mammalian cerebrovascular nerve fibers and dilates pial and peripheral arteries. Neurosci Lett 57:91–95Google Scholar
  40. 40.
    Heyck H (1969) Pathogenesis of migraine. Res Clin Study Headache 2:128Google Scholar
  41. 41.
    Horton BT, Peters GA, Blumenthal LS (1945) New product in the treatment of migraine; preliminary report. Proc Staff Meet Mayo Clin 20:241–248Google Scholar
  42. 42.
    Hoyer D (1988) Molecular pharmacology and biology of 5-HT1C receptors. Trends in Pharmacol Sci 9:89Google Scholar
  43. 43.
    Hoyer D, Engel G, Kalkman HO (1985) Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)-[125H]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. Eur J Pharmacol 118:13–23Google Scholar
  44. 44.
    Humphrey PPA, Feniuk W, Watts AD (1982) Ketanserin — a novel hypertensive drug? J Pharm Pharmacol 34:541Google Scholar
  45. 45.
    Humphrey PPA, Feniuk W, Perren MJ, Connor HE, Oxford AW (1989) The pharmacology of the novel 5-HT1-like receptor agonist, GR43175. Cephalalgia 9(suppl 9):23–33Google Scholar
  46. 46.
    Humphrey PPA, Feniuk W, Perren MJ, Oxford AW, Brittain AT (1989) Sumatriptan succinate. Drugs of the Future 14:35–39Google Scholar
  47. 47.
    Humphrey PPA, Apperley E, Feniuk W, Perren MJ (1990) A rational approach to identifying a fundamentally new drug for the treatment of migraine. In: Saxena PR, Wallis DI, Wouters W, Bevan P (eds) Cardiovascular pharmacology of 5-hydroxytryptamine. Kluwer, Dordrecht, pp 417–431Google Scholar
  48. 48.
    Humphrey PPA, Feniuk W, Perren MJ (1990) Anti-migraine drugs in development: advances in serotonin receptor pharmacology. Headache 30:12–16Google Scholar
  49. 49.
    Humphrey PPA, Feniuk W, Perren MJ (1990) 5-HT in migraine: evidence from 5-HT1-like receptor agonists for a vascular aetiology. In: Sandler M, Collins G (eds) Migraine — a spectrum of ideas. Oxford University Press, Oxford, pp 147–172Google Scholar
  50. 50.
    Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET (1990) Serotonin and migraine. Ann NY Acad Sci 600:587–598Google Scholar
  51. 51.
    Ireland SJ, Tyers MB (1987) Pharmacological characterisation of 5-hydroxytryptamine-induced depolarisation of the rat isolated vagus nerve. Br J Pharmacol 90:229–238Google Scholar
  52. 52.
    Keele CA, Armstrong D (1964) Substances producing pain and itch. Williams and Wilkins, BaltimoreGoogle Scholar
  53. 53.
    Kimball RW, Friedman AP, Valeejo E (1960) Effect of serotonin in migraine patients. Neurology 10:107–111Google Scholar
  54. 54.
    Lance JW (1973) The mechanism and management of headache, 2nd edn. Butterworths, LondonGoogle Scholar
  55. 55.
    Lance JW, Anthony M, Hinterberger H (1967) The control of cranial arteries by humoral mechanisms and its relation to the migraine syndrome. Headache 7:93–102Google Scholar
  56. 56.
    Lataste X, Ferrari MD, Hirt D, Notter M, Wilkinson M (1989) Efficacy and tolerability of ICS 205-930, a 5-HT3 receptor antagonist, in migraine prophylaxis. Cephalalgia 9:346–347Google Scholar
  57. 57.
    Loisy C, Beorchia S, Centonze V, Fozard JR, Schechter PJ, Tell GP (1985) Effects on migraine headache of MDL 72222 an antagonist at neuronal 5-HT receptors. Double-blind, placebocontrolled study. Cephalalgia 5:79–82Google Scholar
  58. 58.
    Moskowitz MA (1984) Neurobiology of vascular head pain. Ann Neurol 16:157–168Google Scholar
  59. 59.
    Moskowitz MA (1987) Sensory connections to cephalic blood vessels and their possible importance to vascular headaches. In: Rose FC (ed) Advances in headache research. John Libbey, London, pp 81–86Google Scholar
  60. 60.
    Moskowitz MA, Reinhard JF, Romero J, Pettibone DJ (1979) Neurotransmitters and the fifth cranial nerve: is there a relation to headache phase of migraine? Lancet II:883–885Google Scholar
  61. 61.
    Muck-Seler D, Deanovic Z, Dupelj M (1979) Platelet serotonin (5-HT) and 5-HT releasing factor in plasma of migrainous patients. Headache 19:14–17Google Scholar
  62. 62.
    Müller-Schweinitzer E, Weidmann H (1978) Basic pharmacological properties. In: Berde B, Schild HO (ed) Ergot alkaloids and related compounds. Handbook of experimental pharmacology. Springer, Berlin, pp 87–232Google Scholar
  63. 63.
    Mylecharane EJ (1991) 5-HT2 receptor antagonists and migraine therapy. J Neurol 238 (suppl 1):S45-S52Google Scholar
  64. 64.
    Nichols FT, Mawad M, Mohr JP, Stein B, Hilal S, Michelsen WJ (1990) Focal headache during balloon inflation in the internal carotid and middle cerebral arteries. Stroke 21:555–559Google Scholar
  65. 65.
    Olesen J (1985) Migraine and regional cerebral blood flow. Trends in Neurol Sci 8:318–320Google Scholar
  66. 66.
    Olesen J, Lauritzen M, Tfelt-Hansen P, Henriksen L, Larsen B (1982) Spreading cerebral oligemia in classical and normal cerebral blood flow in common migraine. Headache 22:242–248Google Scholar
  67. 67.
    Ostfeld AM, Chapman LF, Goodell H, Wolff HG (1957) Studies in headache. Psychosom Med 19:199–208Google Scholar
  68. 68.
    Ostfeld AM, Wolff HG (1955) Studies on headache: arterenol (norepinephrine) and vascular headache of the migraine type. Arch Neurol Psychiatry 74:131–136Google Scholar
  69. 69.
    Page IH (1954) Serotonin (5-hydroxytryptamine). Physiol Rev 34:563–588Google Scholar
  70. 70.
    Peatfield RC (1986) Headache. Springer, BerlinGoogle Scholar
  71. 71.
    Peroutka SJ (1990) The pharmacology of current anti-migraine drugs. Headache 30:5–11Google Scholar
  72. 72.
    Peroutka SJ, McCarthy BG (1989) Sumatriptan (GR43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. Eur J Pharmacol 163:133–136Google Scholar
  73. 73.
    Perrin VL, Färkkilä M, Goasguen J, Doenicke A, Brand J, Tfelt-Hansen P (1989) Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine. Cephalalgia 9 (suppl 9):63–72Google Scholar
  74. 74.
    Pettibone DJ, Williams M (1984) Serotonin-releasing effects of substituted piperazines in vitro. Biochem Pharmacol 33:1531–1535Google Scholar
  75. 75.
    Raskin NH (1981) Pharmacology of migraine. Annu Rev Pharmacol Toxicol 21:463–478Google Scholar
  76. 76.
    Ray BS, Wolff HG (1940) Experimental studies on headache: Pain-sensitive structures of the head and their significance in headache. Arch Surg 41:813–856Google Scholar
  77. 77.
    Remick RA, Keller FD, Gibson RE, Carter D (1989) A comparison between fluoxetine and doxepine in depressed patients. Curr Ther Res 46:842–848Google Scholar
  78. 78.
    Richardson BP, Engel G, Donatsch P, Stadler PA (1985) Identification of 5-hydroxytryptamine M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316:126–131Google Scholar
  79. 79.
    Ryan RE (1968) Double-blind crossover comparison of BC-105, methysergide and placebo in the prophylaxis of migraine headache. Headache 8:118–126Google Scholar
  80. 80.
    Salmon S, Bonciani M, Fanciullacci M, Marianelli L, Michelacci S, Sicuteri F (1982) A putative 5-HT central feedback in migraine and cluster headache attacks. In: Critchley M, Friebman AP, Gurini S, Sicuteri F (eds) Advances in neurology, Vol 33, Headache: physiopathological and clinical concepts. Raven Press, New York, pp 265–274Google Scholar
  81. 81.
    Schumacher GA, Wolff HG (1941) Experimental studies on headache: A. Contrast of histamine headache with the headache of migraine and that associated with hypertension. B. Contrast of vascular mechanisms in preheadache and in headache phenomena of migraine. Arch Neurol Psychiatry 45:199–214Google Scholar
  82. 82.
    Sicuteri F (1959) Prophylactic and therapeutic properties of l-methyl-lysergic acid butanolamide in migraine. Int Arch Allergy 15:300–307Google Scholar
  83. 83.
    Sicuteri F, Testi A, Anselmi B (1961) Biochemical investigations in headache: increase in the hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy 19:55–58Google Scholar
  84. 84.
    Sommerville JM, McLaren EH, Campbell LM, Watson JM (1982) Severe headache and disturbed liver function during treatment with zimelidine. Br Med J 285:1009Google Scholar
  85. 85.
    Syvälahti E, Kangasniemi P, Ross B (1979) Migraine headache and blood serotonin levels after administration of zimelidine, a selective inhibitor of serotonin uptake. Curr Ther Res 25:299–310Google Scholar
  86. 86.
    Trautmann E (1928) Die Beeinflussung migräneartiger Zustände durch ein sympathikushemmendes Mittel (Gynergen). Munch Med Wochenschr 75:513Google Scholar
  87. 87.
    Tzanck A (1928) Le traitement des migraines par le tartrate d'ergotamine. Bull Soc Med Paris 52:1057–1061Google Scholar
  88. 88.
    Verbeuren TJ (1990) The distribution and biochemistry of 5-hydroxytryptamine in the cardiovascular system. In: Saxena PR, Wallis DI, Wouters W, Bevan P (eds): Cardiovascular pharmacology of 5-hydroxytryptamine: prospective therapeutic applications. Kluwer, Dordrecht, pp 3–13Google Scholar
  89. 89.
    White JC, Sweet WH (1955) Pain: its mechanisms and neurosurgical control. CC Thomas, SpringfieldGoogle Scholar
  90. 90.
    Winther K (1985) Ketanserin — a selective serotonin antagonist, in relation to platelet aggregation and migraine attack rate. Cephalalgia 5(suppl 3):402–403Google Scholar
  91. 91.
    Wolff HS (1963) Headache and other head pain. Oxford University Press, OxfordGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • P. P. A. Humphrey
    • 1
  1. 1.Pharmacology DivisionGlaxo Group Research LtdWareUK

Personalised recommendations