Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 350, Issue 3, pp 225–229 | Cite as

5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives

  • John R. Fozard
  • Hans O. Kalkman
Invited Review


The hypothesis that 5-hydroxytryptamine (5-HT) acting through 5-HT2c receptors is a key factor in the initiation of migraine has been re-evaluated in the light of recent basic and clinical scientific developments. The key findings are that nitric oxide is an important trigger for migraine, that 5-HT2B/5-HT2C receptors are present on endothelial cells and trigger nitric oxide release when activated and that supersensitivity of the 5-HT2B/5-HT2C receptor is a neurochemical feature predisposing to headache. Taken together the data bring new perspectives to the role of 5-HT acting through 5-HT2C (or closely similar) receptors in the initiation of migraine.

Key words

Migraine Nitric oxide Endothelium 5-HT2C Receptors 5-HT2B Receptors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bodelsson M, Törnebrandt K, Arneklo-Nobin B (1993) Endothelial relaxing 5-hydroxytryptamine receptors in the rat jugular vein: similarity with the 5-hydroxytryptamine1c receptor. J Pharmacol Exp Ther 264:709–716Google Scholar
  2. Bredberg U, Eyjolfsdottir GS, Paalzow L, Tfelt-Hansen P, Tfelt-Hansen V (1986) Pharmacokinetics of methysergide and its metabolite methylergometrin in man. Eur J Clin Pharmacol 30:75–77Google Scholar
  3. Bradley PB, Engel G, Feniuk W Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology 25:563–576Google Scholar
  4. Brewerton TD, Murphy DL, Mueller EA, Jimerson DC (1988) Induction of migraine like headaches by the serotonin agonist m-chlorophenylpiperazine. Clin Pharmacol Ther 43:605–609Google Scholar
  5. Brewerton TD, Murphy DL, Lesem MD, Brandt HA, Jimerson DC (1992) Headache responses following m-chlorophenylpiperazine in bulimics and controls. Headache 32:217–222Google Scholar
  6. Clineschmidt BV, Reiss DR, Pettibone DJ, Robinson JL (1985) Characterization of 5-hydroxytryptamine receptors in rat stomach fundus. J Pharmacol Exp Ther 235:696–708Google Scholar
  7. Cohen ML, Wittenauer LA (1986) Further evidence that the serotonin receptor in the rat stomach fundus is not 5-HT1A or 5-HT1B. Life Sci 38:1–5Google Scholar
  8. Ferrari MD, Saxena PR (1993) On Serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13:151–165Google Scholar
  9. Foguet M, Hoyer D, Pardo LA, Parekh A, Kluxen FW, Kalkman HO, Stühmer W, Lübbert H (1992) Cloning and functional characterization of the rat stomach fundus serotonin receptor. EMBO J 11:3481–3487Google Scholar
  10. Fozard JR (1982) Serotonin, migraine and platelets. In: Van Zwieten PA, Schönbaum E (eds) Drugs and platelets. Gustav Fischer Verlag, Stuttgart, pp 135–146Google Scholar
  11. Fozard JR (1985) 5-Hydroxytryptamine in the pathophysiology of migraine. In: Bevan JA, Godfraind T, Maxwell RA, Stocklet JL, Worcel M (eds) Vascular neuroeffector mechanisms. Elsevier, Amsterdam, pp 321–328Google Scholar
  12. Fozard JR (1990) 5-HT in migraine: evidence from 5-HT receptor antagonists for a neuronal aetiology. In: Sandler M, Collins GM (eds) Migraine: a spectrum of ideas. Oxford University Press, Oxford, pp 128–146Google Scholar
  13. Fozard JR (1992) 5-HT1C receptor agonism as an initiating event in migraine. In: Olesen J, Saxena PR (eds) 5-Hydroxytryptamine mechanisms in primary headache. Raven Press, New York, pp 200–212Google Scholar
  14. Fozard JR, Gray JA (1989) 5-HT1c receptor activation: a key step in the initiation of migraine? Trends Pharmacol Sci 10:307–309Google Scholar
  15. Glusa E, Richter M (1993) Endothelium-dependent relaxation of porcine pulmonary arteries via 5-HT1C-like receptors. Naunyn-Schmiedeberg's Arch Pharmacol 347:471–477Google Scholar
  16. Gordon ML, Lipton RB, Brown S-L, Nakraseire C, Russell M, Pollack SZ, Korn ML, Merriam A, Solomon S, van Praag HM (1993) Headache and cortisol responses to m-chlorophenylpiperazine are highly correlated. Cephalalgia 13:400–405Google Scholar
  17. Hartig PR, Hoffman BJ, Kaufman MJ, Hirato F (1990) The 5-HT1C receptor. Ann NY Acad Sci 600:149–167Google Scholar
  18. Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Recept Res 8:59–81Google Scholar
  19. Humphrey PPA (1991) 5-Hydroxytryptamine and the pathophysiology of migraine. J Neurol 238:S38-S44Google Scholar
  20. Humphrey PPA, Feniuk W Perren MJ, Beresford IJM, Skingle M, Whalley ET (1990) Serotonin and migraine. Ann NY Acad Sci 600:587–600Google Scholar
  21. Humphrey PPA, Hartig PR, Hoyer D (1993) A proposed new nomenclature for 5-HT receptors. Trends Pharmacol Sci 14:233–236CrossRefPubMedGoogle Scholar
  22. Hughes SR, Brain SD (1994) Nitric oxide-dependent release of vasodilator quantities of calcitonin gene-related peptide from capsaicin-sensitive nerves in rabbit skin. Br J Pharmacol 111:425–430Google Scholar
  23. Ialenti A, Ianaro A, Moncada S, Di Rosa M (1992) Modulation of acute inflammation by endogenous nitric oxide. Eur J Pharmacol 211:177–182Google Scholar
  24. Kahn RS, Wetzler S (1991) m-Chlorophenylpiperazine as a probe of serotonin function. Biol Psychiatr 30:1139–1166Google Scholar
  25. Kahn RS, Kalus O, Wetzler S, Cahn W Asnis GM, van Praag HM (1990) Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects. Psychiatr Res 33:189–198Google Scholar
  26. Kalkman HO (1994) Is migraine prophylactic activity caused by 5-HT2B or 5-HT2C receptor blockade? Life Sci 54:641–644Google Scholar
  27. Kalkman HO, Fozard JR (1991) Further definition of the 5-HT receptor mediating contraction of the rat stomach fundus: relation to 5-HT1D recognition sites. In: Fozard JR, Saxena PR (eds) Serotonin: molecular biology, receptors and functional effects. Birkhauser, Basel, pp 153–160Google Scholar
  28. Krabbe AA, Olesen J (1990) Headache provocation by continuous intravenous infusion of histamine. Clinical results and receptor mechanisms. Pain 8:253–259Google Scholar
  29. Kuo HP, Liu S, Barnes PJ (1992) The effect of endogenous nitric oxide on neurogenic plasma exudation in guinea-pig airways. Eur J Pharmacol 221:385–388Google Scholar
  30. Kursar JD, Nelson DL, Wainscott DB, Cohen ML, Baez M (1992) Molecular cloning, functional expression, and pharmacological characterization of a novel serotonin receptor (5-hydroxytryptamine2F) from rat stomach fundus. Mol Pharmacol 92:549–557Google Scholar
  31. Lance JW Lambert GA, Goadsby PJ, Zagami AS (1989) 5-Hydroxytryptamine and its putative aetiological involvement in migraine. Caphalalgia 9 [Suppl 9]:7–13Google Scholar
  32. Leff P, Martin GR, Morse JM (1987) Differential classification of vascular smooth muscle and endothelial cell 5-HT receptors by use of tryptamine analogues. Br J Pharmacol 91:321–331Google Scholar
  33. Lippe IT, Stabentheiner A, Holzer P (1993) Participation of nitric oxide in the mustard oil-induced neurogenic inflammation of the rat paw skin. Eur J Pharmacol 232:113–120Google Scholar
  34. Martin GR, Browning C, Giles M (1993) Further characterisation of an atypical 5-HT receptor mediating endothelium-dependent vasorelaxation. Br J Pharmacol 110:137PGoogle Scholar
  35. Moskowitz MA (1992a) Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 13:307–311Google Scholar
  36. Moskowitz MA (1992b) Interpreting vessel diameter changes in vascular headaches. Cephalalgia 12:5–7Google Scholar
  37. Mueller EA, Murphy DL, Sunderland T (1986) Further studies of the putative serotonin agonist, m-chlorophenylpiperazine: Evidence for a serotonin receptor mediated mechanism of action in humans. Psychopharmacology 89:388–391Google Scholar
  38. Olesen J, Iversen HK, Thomsen LL (1993) Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. NeuroReport 4:1027–1030Google Scholar
  39. Peatfield RC, Fozard JR, Clifford Rose F (1986) Drug treatment of migraine. In: Clifford Rose F (ed) Handbook of clinical neurology, vol 4: headache. Elsevier, Amsterdam, pp 173–216Google Scholar
  40. Pigott TA, Zohar J, Hill JL, Bernstein SE, Grover GN, Zohar-Kadouch RC, Murphy DL (1991) Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with absessive-compulsive disorder. Biol Psychiatr 29:418–426Google Scholar
  41. Saxena PR, Ferrari MD (1989) 5-HT1-like receptor agonists and the pathophysiology of migraine. Trends Pharmacol Sci 10:200–204Google Scholar
  42. Schmuck K, Ullmer C, Engels P, Lübbert H (1994) Cloning and functional characterization of the human 5-HT2B serotonin receptor. FEBS Lett 324:85–90Google Scholar
  43. Seibyl JP, Krystal JH, Price LH, Woods SW, D'Amico C, Heninger GR, Charney DS (1991) Effects of ritanserin on the behavioral, neuroendocrine and cardiovascular responses to metachlorophenylpiperazine in healthy human subjects. Psychiatr Res 38:227–236Google Scholar
  44. Siberstein SB, Fozard JR, Murphy DL (1992) More on mCPP and migraine. Headache 32:242–244Google Scholar
  45. Spierings ELH (1991) Hypothesis: serotonin-1 C receptor activation in migraine: an alternative point of view with therapeutic implication. Headache 31:546–549Google Scholar
  46. Stensrud P, Sjaastad O (1976) Short-term clinical trial of propranolol in racemic from (Inderal), D-propranolol and placebo in migraine. Acta Neurol Scand 53:229–232Google Scholar
  47. Sumner MJ (1991) Characterization of 5-HT receptor mediating endothelium-dependent relaxation in porcine vena cava. Br J Pharmacol 102:938–942Google Scholar
  48. Wainscott DB, Cohen ML, Schenck KW, Audia JE, Nissen JS, Baez M, Kursar JD, Lucaites VL, Nelson DL (1993) Pharmacological characteristics of the newly cloned rat 5-hydroxytryptamine2F receptor. Mol Pharmacol 43:419–426Google Scholar
  49. Walle T, Conradi EC, Walle UK, Fagan TC, Gaffney TE (1978) The predictable relationship between plasma levels and dose during chronic propranolol therapy. Clin Pharmacol Ther 24:668–677Google Scholar
  50. Weerasuriya K, Patel L, Turner P (1982) β-adrenoceptor blockade and migraine. Cephalalgia 2:33–45Google Scholar
  51. Wei EP, Moskowitz MA, Boccalini P, Kontos HA (1992) Calcitonin gene-related peptide mediates mitroglycerine and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 70:1313–1319Google Scholar
  52. Winther K (1985) Ketanserin a selective serotonin antagonist, in relation to platelet aggregation and migraine attack rate. Cephalalgia 5:402–403Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • John R. Fozard
    • 1
  • Hans O. Kalkman
    • 1
  1. 1.Preclinical ResearchSandoz Pharma Ltd.BaselSwitzerland

Personalised recommendations