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Can we Develop Neurally Acting Drugs for the Treatment of Migraine?

Nature Reviews Drug Discovery volume 4, pages 741–750 (2005)Cite this article

Key Points

  • Migraine is a common and often disabling disorder that is increasingly being recognized as a fundamentally neurological problem.

  • Brain-imaging data indicate that the brainstem is pivotal in the pathophysiology of the disorder and, together with the electrophysiological data and the pan-sensory disturbance, a dysfunction of the thalamic processing of afferent traffic is a plausible way of explaining a large part of the problem.

  • For pain processing, the trigeminocervical complex is pivotal and provides an attractive entirely neural target for therapy.

  • This review describes why migraine is a central nervous system problem, and discusses the main approaches that will lead to non-vascular neurally acting treatments for this common and important neurological condition.

  • The potential targets for such an action include calcitonin gene-related peptide (CGRP) receptors, 5-HT1F and 5-HT1D receptors, glutamate receptors, adenosine A1 receptors, nociceptin, vanilloid transient-receptor potential V1 (TRPV1) receptors, cannabinoid CB1 receptors, orexin receptors and nitric oxide (NO)-based mechanisms.

Abstract

Serotonin (5-HT)1B/1D receptor agonists, which are also known as triptans, represent the most important advance in migraine therapeutics in the four millennia that the condition has been recognized. The vasoconstrictive activity of triptans produced a small clinical penalty in terms of coronary vasoconstriction but also raised an enormous intellectual question: to what extent is migraine a vascular problem? Functional neuroimaging and neurophysiological studies have consistently developed the theme of migraine as a brain disorder and, therefore, demanded that the search for neurally acting antimigraine drugs should be undertaken. The prospect of non-vasoconstrictor acute migraine therapies, potential targets for which are discussed here, offers a real opportunity to patients and provides a therapeutic rationale that places migraine firmly in the brain as a neurological problem, where it undoubtedly belongs.

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Figure 1: Imaging studies of migraine.
Figure 2: The dorsolateral pons and migraine.
Figure 3: Selected pathways and modulatory centres associated with migraine.

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Article 13 January 2022

Michel D. Ferrari, Peter J. Goadsby, … David W. Dodick

References

  1. Lipton, R. B., Stewart, W. F., Diamond, S., Diamond, M. L. & Reed, M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41, 646–657 (2001).

    CAS  PubMed  Google Scholar 

  2. Menken, M., Munsat, T. L. & Toole, J. F. The global burden of disease study: implications for neurology. Arch. Neurol. 57, 418–420 (2000).

    CAS  PubMed  Google Scholar 

  3. Goadsby, P. J., Lipton, R. B. & Ferrari, M. D. Migraine: current understanding and treatment. N. Engl. J. Med. 346, 257–270 (2002). An overall review of migraine pathophysiology and treatment.

    CAS  PubMed  Google Scholar 

  4. Lance, J. W. & Goadsby, P. J. Mechanism and Management of Headache (Elsevier, New York, 2005). The latest (seventh) edition of a popular book with an overview of headache.

    Google Scholar 

  5. Goadsby, P. J. The pharmacology of headache. Prog. Neurobiol. 62, 509–525 (2000).

    CAS  PubMed  Google Scholar 

  6. Doenicke, A., Siegel, E., Hadoke, M. & Perrin, V. L. Initial clinical study of AH25086B (5-HT1-like agonist) in the acute treatment of migraine. Cephalalgia 7, 437–438 (1987).

    Google Scholar 

  7. Doenicke, A., Brand, J. & Perrin, V. L. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1, 1309–1311 (1988).

    CAS  PubMed  Google Scholar 

  8. Ferrari, M. D. & The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N. Engl. J. Med. 325, 316–321 (1991).

    Google Scholar 

  9. Dodick, D. et al. Consensus statement: cardiovascular safety profile of triptans (5-HT1B/1D agonists) in the acute treatment of migraine. Headache 44, 414–425 (2004).

    Google Scholar 

  10. Ferrari, M. D., Roon, K. I., Lipton, R. B. & Goadsby, P. J. Oral triptans (serotonin, 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358, 1668–1675 (2001). This paper compares the main triptans according to their efficacy and side effect endpoints.

    CAS  PubMed  Google Scholar 

  11. Ferrari, M. D., Goadsby, P. J., Roon, K. I. & Lipton, R. B. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 22, 633–658 (2002).

    CAS  PubMed  Google Scholar 

  12. Goadsby, P. J. Post-triptan era for the treatment of acute migraine. Curr. Pain Headache Rep. 8, 393–398 (2004).

    PubMed  Google Scholar 

  13. Cohen, A. S. & Goadsby, P. J. Functional neuroimaging of primary headache disorders. Curr. Neurol. Neurosci. Rep. 4, 105–110 (2004).

    PubMed  Google Scholar 

  14. Hadjikhani, N. et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl Acad. Sci. USA 98, 4687–4692 (2001). An important paper that images migraine aura and provides compelling evidence for its similarity to CSD.

    CAS  PubMed  Google Scholar 

  15. Kaube, H. & Giffin, N. J. The electrophysiology of migraine. Curr. Opin. Neurol. 15, 303–309 (2002).

    PubMed  Google Scholar 

  16. Ambrosini, A. & Schoenen, J. The electrophysiology of migraine. Curr. Opin. Neurol. 16, 327–331 (2003).

    PubMed  Google Scholar 

  17. Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nature Med. 1, 658–660 (1995).

    CAS  PubMed  Google Scholar 

  18. Welch, K. M., Nagesh, V., Aurora, S. & Gelman, N. Periaqueductal grey matter dysfunction in migraine: cause or the burden of illness? Headache 41, 629–637 (2001).

    CAS  PubMed  Google Scholar 

  19. Goadsby, P. J. Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine. Cephalalgia 22, 107–111 (2002).

    CAS  PubMed  Google Scholar 

  20. Haas, D. C., Kent, P. F. & Friedman, D. I. Headache caused by a single lesion of multiple sclerosis in the periaqueductal gray area. Headache 33, 452–455 (1993).

    CAS  PubMed  Google Scholar 

  21. Raskin, N. H., Hosobuchi, Y. & Lamb, S. Headache may arise from perturbation of brain. Headache 27, 416–420 (1987).

    CAS  PubMed  Google Scholar 

  22. Veloso, F., Kumar, K. & Toth, C. Headache secondary to deep brain implantation. Headache 38, 507–515 (1998).

    CAS  PubMed  Google Scholar 

  23. Knight, Y. E. & Goadsby, P. J. The periaqueductal gray matter modulates trigeminovascular input: a role in migraine? Neuroscience 106, 793–800 (2001).

    CAS  PubMed  Google Scholar 

  24. Knight, Y. E., Bartsch, T. & Goadsby, P. J. Trigeminal antinociception induced by bicuculline in the periaqueductal grey (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci. Lett. 336, 113–116 (2003).

    CAS  PubMed  Google Scholar 

  25. Knight, Y. E., Bartsch, T., Kaube, H. & Goadsby, P. J. P/Q-type calcium channel blockade in the PAG facilitates trigeminal nociception: a functional genetic link for migraine? J. Neurosci. 22, 1–6 (2002). This important paper illustrates the principle that brain dysfunction without peripheral change can produce alterations in pain-pathway function.

    Google Scholar 

  26. Bandler, R. & Keay, K. A. Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Progress Brain Res. 107, 285–300 (1996).

    CAS  Google Scholar 

  27. Bartsch, T., Knight, Y. E. & Goadsby, P. J. Activation of 5-HT1B/1D receptors in the periaqueductal grey inhibits meningeal nociception. Ann. Neurol. 56, 371–381 (2004). An extremely important paper that provides a new possible locus of action for triptans and opens up the possibility of a non-trigeminal function.

    CAS  PubMed  Google Scholar 

  28. Afridi, S. & Goadsby, P. J. New onset migraine with a brainstem cavernous angioma. J. Neurol. Neurosurg. Psychiatr. 74, 680–682 (2003).

    CAS  Google Scholar 

  29. Bahra, A., Matharu, M. S., Buchel, C., Frackowiak, R. S. J. & Goadsby, P. J. Brainstem activation specific to migraine headache. Lancet 357, 1016–1017 (2001).

    CAS  PubMed  Google Scholar 

  30. Afridi, S. et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Cephalalgia 24, 775–776 (2004).

    Google Scholar 

  31. Afridi, S. et al. A PET study in spontaneous migraine. Arch. Neurol. 62, 1270–1275 (2005).

    PubMed  Google Scholar 

  32. Amaral, D. G. & Sinnamon, H. M. The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog. Neurobiol. 9, 147–196 (1977).

    CAS  PubMed  Google Scholar 

  33. Goadsby, P. J., Lambert, G. A. & Lance, J. W. Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res. 249, 247–254 (1982).

    CAS  PubMed  Google Scholar 

  34. Goadsby, P. J. & Duckworth, J. W. Low frequency stimulation of the locus coeruleus reduces regional cerebral blood flow in the spinalized cat. Brain Res. 476, 71–77 (1989).

    CAS  PubMed  Google Scholar 

  35. May, A., Bahra, A., Buchel, C., Frackowiak, R. S. J. & Goadsby, P. J. Hypothalamic activation in cluster headache attacks. Lancet 352, 275–278 (1998). This was the first paper to show posterior hypothalamic region activity in cluster headache.

    CAS  PubMed  Google Scholar 

  36. May, A. et al. Experimental cranial pain elicited by capsaicin: a PET-study. Pain 74, 61–66 (1998).

    CAS  PubMed  Google Scholar 

  37. Tracey, I. et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J. Neurosci. 22, 2748–2752 (2002).

    CAS  PubMed  Google Scholar 

  38. Schoenen, J., Ambrosini, A., Sandor, P. S. & Maertens de Noordhout, A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin. Neurophysiol. 114, 955–972 (2003).

    PubMed  Google Scholar 

  39. Afra, J., Sandor, P. & Schoenen, J. Habituation of visual and intensity dependence of cortical auditory evoked potentials tend to normalise just before and during migraine attacks. Cephalalgia 20, 347 (2000).

    Google Scholar 

  40. Proietti-Cecchini, A., Afra, J. & Schoenen, J. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 17, 849–854 (1997).

    CAS  PubMed  Google Scholar 

  41. Schoenen, J., Wang, W., Albert, A. & Delwaide, P. J. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur. J. Neurol. 2, 115–122 (1995).

    CAS  PubMed  Google Scholar 

  42. Wang, W. & Schoenen, J. Interictal potentiation of passive 'oddball' auditory event-related potentials in migraine. Cephalalgia 18, 261–265 (1998). This important paper illustrates the typical electrophysiological defect in migraine dyshabituation.

    CAS  PubMed  Google Scholar 

  43. Niebur, E., Hsiao, S. S. & Johnson, K. O. Synchrony: a neural mechanism for attentional selection? Curr. Opin. Neurobiol. 12, 190–194 (2002). This fascinating paper sets out the possible mechanisms for neural synchrony.

    CAS  PubMed  Google Scholar 

  44. Angelini, L. et al. Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys. Rev. Lett. 93, 038103-1–038103-4 (2004).

  45. Goadsby, P. J. Migraine pathophysiology: the brainstem governs the cortex. Cephalalgia 23, 565–566 (2003).

    Google Scholar 

  46. Schoenen, J. & Timsit-Berthier, M. Contingent negative variation: methods and potential interest in headache. Cephalalgia 13, 28–32 (1993).

    CAS  PubMed  Google Scholar 

  47. Kropp, P. & Gerber, W. D. Prediction of migraine attacks using a slow cortical potential, the contingent negative variation. Neurosci. Lett. 257, 73–76 (1998).

    CAS  PubMed  Google Scholar 

  48. Maertens de Noordhout, A., Timsit-Berthier, M. & Schoenen, J. Contingent negative variation (CNV) in migraineurs before and during prophylactic treatment with β-blockers. Cephalalgia 5, 34–35 (1985). This important paper illustrates an electrophysiological trait of migraine that can be reversed by a preventive treatment.

    Google Scholar 

  49. Gantenbein, A., Goadsby, P. J. & Kaube, H. Introduction of a clinical scoring system for migraine research applied to electrophysiological studies. Cephalalgia 24, 1095–1096 (2004).

    Google Scholar 

  50. Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders (second edition). Cephalalgia 24, 1–160 (2004). This paper gives contemporary definitions for all headache types.

  51. Olesen, J. et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann. Neurol. 28, 791–798 (1990). A ground-breaking observation of blood-flow changes in migraine with aura that led to the spreading depression hypothesis.

    CAS  PubMed  Google Scholar 

  52. Cutrer, F. M. et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann. Neurol. 43, 25–31 (1998). This extremely important observation expanded on earlier flow work and led to a non-ambiguous method that confirmed spreading depression as the substrate for migraine aura.

    CAS  PubMed  Google Scholar 

  53. Leao, A. A. P. Spreading depression of activity in cerebral cortex. J. Neurophysiol. 7, 359–390 (1944).

    Google Scholar 

  54. Leao, A. A. P. Pial circulation and spreading activity in the cerebral cortex. J. Neurophysiol. 7, 391–396 (1944).

    Google Scholar 

  55. Lauritzen, M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 (1994).

    PubMed  Google Scholar 

  56. Moskowitz, M. A., Bolay, H. & Dalkara, T. Deciphering migraine mechanisms: clues from familial hemiplegic migraine genotypes. Ann. Neurol. 55, 276–280 (2004).

    CAS  PubMed  Google Scholar 

  57. Goadsby, P. J. Migraine, aura and cortical spreading depression: why are we still talking about it? Ann. Neurol. 49, 4–6 (2001).

    CAS  PubMed  Google Scholar 

  58. De Vries, P., Villalon, C. M. & Saxena, P. R. Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur. J. Pharmacol. 375, 61–74 (1999).

    CAS  PubMed  Google Scholar 

  59. Goadsby, P. J. & Kaube, H. in The Headaches 2nd edn (eds Olesen, J., Tfelt-Hansen, P. & Welch, K. M. A.) 195–202 (Lippincott Williams & Wilkins, Philadelphia, 2000).

    Google Scholar 

  60. Saxena, P. R. & De Boer, M. O. Pharmacology of antimigraine drugs. J. Neurol. 238, S28–S35 (1991).

    PubMed  Google Scholar 

  61. Saxena, P. R. & Cairo-Rawlins, W. I. Presynaptic inhibition by ergotamine of the responses to cardioaccelerator nerve stimulations in the cat. Eur. J. Pharmacol. 58, 305–312 (1979).

    CAS  PubMed  Google Scholar 

  62. Markowitz, S., Saito, K. & Moskowitz, M. A. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. J. Neurosci. 7, 4129–4136 (1987).

    CAS  PubMed  Google Scholar 

  63. Markowitz, S., Saito, K. & Moskowitz, M. A. Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia 8, 83–91 (1988).

    CAS  PubMed  Google Scholar 

  64. Williamson, D. J., Hargreaves, R. J., Hill, R. G. & Shepheard, S. L. Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat- intravital microscope studies. Cephalalgia 17, 525–531 (1997).

    CAS  PubMed  Google Scholar 

  65. Kaube, H., Hoskin, K. L. & Goadsby, P. J. Activation of the trigeminovascular system by mechanical distension of the superior sagittal sinus in the cat. Cephalalgia 12, 133–136 (1992).

    CAS  PubMed  Google Scholar 

  66. Burstein, R. & Jakubowski, M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitisation. Ann. Neurol. 55, 27–36 (2004).

    CAS  PubMed  Google Scholar 

  67. Selby, G. & Lance, J. W. Observations on 500 cases of migraine and allied vascular headache. J. Neurol. Neurosurg. Psychiatr. 23, 23–32 (1960).

    CAS  Google Scholar 

  68. Tfelt-Hansen, P. et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123, 9–18 (2000).

    PubMed  Google Scholar 

  69. Buzzi, M. G. & Moskowitz, M. A. Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia 11, 165–168 (1991).

    CAS  PubMed  Google Scholar 

  70. Hoskin, K. L., Kaube, H. & Goadsby, P. J. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiology study. Brain 119, 249–256 (1996).

    PubMed  Google Scholar 

  71. Read, S. J., Smith, M. I., Hunter, A. J., Upton, N. & Parsons, A. A. SB-220453, a potential novel antimigraine compound, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat. Cephalalgia 20, 92–99 (1999).

    Google Scholar 

  72. Smith, M. I. et al. Repetitive cortical spreading depression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453. Cephalalgia 20, 546–53 (2000).

    CAS  PubMed  Google Scholar 

  73. MaassenVanDenBrink, A. et al. The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan. Cephalalgia 20, 538–545 (2000).

    CAS  PubMed  Google Scholar 

  74. Parsons, A. A. et al. Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reflexes. Br. J. Pharmacol. 132, 1549–1557 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Diener, H. C. et al. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J. Neurol. 251, 943–950 (2004).

    CAS  PubMed  Google Scholar 

  76. Brandes, J. L. et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 291, 965–973 (2004).

    CAS  PubMed  Google Scholar 

  77. Silberstein, S. D., Neto, W., Schmitt, J. & Jacobs, D. Topiramate in migraine prevention: results of a large controlled trial. Arch. Neurol. 61, 490–495 (2004).

    PubMed  Google Scholar 

  78. Akerman, S. & Goadsby, P. J. Topiramate inhibits cortical spreading depression in rat and cat: a possible contribution to its preventive effect in migraine. Cephalalgia 24, 783–784 (2004).

    Google Scholar 

  79. Tvedskov, J. F., Iversen, H. K. & Olesen, J. A double-blind study of SB-220453 (Tonerbasat) in the glyceryltrinitrate (GTN) model of migraine. Cephalalgia 24, 875–882 (2004).

    CAS  PubMed  Google Scholar 

  80. Tvedskov, J. F. et al. The effect of propranolol on glyceryltrinitrate-induced headache and arterial response. Cephalalgia 24, 1076–1087 (2004).

    CAS  PubMed  Google Scholar 

  81. Tvedskov, J. F. et al. The prophylactic effect of valproate on glyceryltrinitrate induced migraine. Cephalalgia 24, 576–585 (2004).

    CAS  PubMed  Google Scholar 

  82. Storer, R. J. & Goadsby, P. J. Topiramate inhibits trigeminovascular neurons in the cat. Cephalalgia 24, 1049–1056 (2004).

    CAS  PubMed  Google Scholar 

  83. Ophoff, R. A. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 (1996). This ground-breaking report of the first clear genetic defect in a migraine syndrome pointed to the principle of migraine as a channelopathy.

    CAS  PubMed  Google Scholar 

  84. van den Maagdenberg, A. M. J. M. et al. A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701–710 (2004). An excellent example of a translational work that shows the effects of a human mutation in a mouse model.

    CAS  PubMed  Google Scholar 

  85. Shank, R. P., Gardocki, J. F., Streeter, A. J. & Maryanoff, B. E. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41, S3–S9 (2000).

    CAS  PubMed  Google Scholar 

  86. Geer, J. J., Dooley, D. J. & Adams, M. E. K(+)-stimulated 45Ca2+ flux into rat neocortical mini-slices is blocked by omega-Aga-IVA and the dual Na+/Ca2+ channel blockers lidoflazine and flunarizine. Neurosci. Lett. 158, 97–100 (1993).

    CAS  PubMed  Google Scholar 

  87. Ebersberger, A., Portz, S., Meissner, W., Schaible, H. G. & Richter, F. Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. Cephalalgia 24, 250–261 (2004).

    CAS  PubMed  Google Scholar 

  88. Shields, K. G., Storer, R. J., Akerman, S. & Goadsby, P. J. Calcium channels modulate nociceptive transmission in the trigeminal nucleus of the cat. Neuroscience (in the press).

  89. Akerman, S., Williamson, D. & Goadsby, P. J. Voltage-dependent calcium channels are involved in neurogenic dural vasodilation via a pre-synaptic transmitter release mechanism. Br. J. Pharmacol. 140, 558–566 (2003).

    CAS  PubMed  Google Scholar 

  90. Kimball, R. W., Friedman, A. P. & Vallejo, E. Effect of serotonin in migraine patients. Neurology 10, 107–111 (1960).

    CAS  PubMed  Google Scholar 

  91. Lance, J. W., Anthony, M. & Hinterberger, H. The control of cranial arteries by humoral mechanisms and its relation to the migraine syndrome. Headache 7, 93–102 (1967).

    CAS  PubMed  Google Scholar 

  92. Humphrey, P. P. A. et al. Serotonin and migraine. Ann. NY Acad. Sci. 600, 587–598 (1990). This paper presents a good summary of the development of sumatriptan from the perspective of the inventors.

    CAS  PubMed  Google Scholar 

  93. Lance, J. W., Fine, R. D. & Curran, D. A. An evaluation of methysergide in the prevention of migraine and other vascular headache. Med. J. Aust. 1, 814–818 (1963).

    Google Scholar 

  94. Johnston, B. M. & Saxena, P. R. The effect of ergotamine on tissue blood flow and the arteriovenous shunting of radioactive microspheres in the head. Br. J. Pharmacol. 63, 541–549 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Phebus, L. A. et al. Characterization of LY334370 as a pharmacological tool to study 5HT1F receptors- binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. Life Sci. 61, 2117–2126 (1997).

    CAS  PubMed  Google Scholar 

  96. Johnson, K. W. et al. 5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. NeuroReport 8, 2237–2240 (1997).

    CAS  PubMed  Google Scholar 

  97. Cohen, M. L. & Schenck, K. 5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein. J. Pharmacol. Exp. Ther. 290, 935–939 (1999).

    CAS  PubMed  Google Scholar 

  98. Razzaque, Z. et al. Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation. Br. J. Clin. Pharmacol. 47, 75–82 (1999).

    CAS  PubMed  Google Scholar 

  99. Goldstein, D. J. et al. Selective serotonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet 358, 1230–1234 (2001). This was the first clinical study of a 5-HT 1F receptor agonist in migraine.

    CAS  PubMed  Google Scholar 

  100. Castro, M. E. et al. Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord. Neuropharmacology 36, 535–542 (1997).

    CAS  PubMed  Google Scholar 

  101. Pascual, J., Arco, C. D., Romon, T., Olmo, C. D. & Pazos, A. [3H] Sumatriptan binding sites in human brain: regional-dependent labelling of 5HT1D and 5HT1F receptors. Eur. J. Pharmacol. 295, 271–274 (1996).

    CAS  PubMed  Google Scholar 

  102. Waeber, C. & Moskowitz, M. A. [3H]sumatriptan labels both 5-HT1D and 5HT1F receptor bindings sites in the guinea pig brain: an autoradiographic study. Naunyn Schmiedebergs Arch. Pharmacol. 352, 263–275 (1995).

    CAS  PubMed  Google Scholar 

  103. Fugelli, A., Moret, C. & Fillion, G. Autoradiographic localization of 5-HT1E and 5-HT1F binding sites in rat brain: effect of serotonergic lesioning. J. Recept. Sig. Transduct. Res. 17, 631–645 (1997).

    CAS  Google Scholar 

  104. Bouchelet, I., Cohen, Z., Case, B. & Hamel, E. Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. Mol. Pharmacol. 50, 219–223 (1996).

    CAS  PubMed  Google Scholar 

  105. Mitsikostas, D. D., Sanchez del Rio, M., Moskowitz, M. A. & Waeber, C. Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis. Eur. J. Pharmacol. 369, 271–277 (1999).

    CAS  PubMed  Google Scholar 

  106. Goadsby, P. J. & Classey, J. D. Evidence for 5-HT1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience 122, 491–498 (2003). This study dissects out the contribution of 5-HT 1B , 5-HT 1D and 5-HT 1F receptors to the inhibition of trigeminovascular neurons.

    CAS  PubMed  Google Scholar 

  107. Maneesi, S., Akerman, S., Lasalandra, M. P., Classey, J. D. & Goadsby, P. J. Electron microscopic demonstration of pre- and postsynaptic 5-HT1D and 5-HT1F receptor immunoreactivity (IR) in the rat trigeminocervical complex (TCC) new therapeutic possibilities for the triptans. Cephalalgia 24, 148 (2004).

    Google Scholar 

  108. McCall, R. B. et al. Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT 1D receptor agonist PNU-142633. Cephalalgia 22, 799–806 (2002).

    CAS  PubMed  Google Scholar 

  109. McCall, R. B. Trigeminal ganglion elicited increases in nucleus trigeminal caudalis blood flow: a novel migraine model. Brain Res. 775, 189–192 (1997).

    CAS  PubMed  Google Scholar 

  110. Waeber, C., Cutrer, F. M., Yu, X.-J. & Moskowitz, M. A. The selective 5HT1D receptor agonist U-109291 blocks dural plasma extravasation and c-fos expression in the trigeminal nucleus caudalis. Cephalalgia 17, 401 (1997).

    Google Scholar 

  111. Potrebic, S., Ahan, A. H., Skinner, K., Fields, H. L. & Basbaum, A. I. Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J. Neurosci. 23, 10988–10997 (2003).

    CAS  PubMed  Google Scholar 

  112. Ahn, A. H., Fields, H. L. & Basbaum, A. I. The triptan receptor 5HT1D is dynamically regulated in the central terminal of primary afferents in models of pain. Neurology 62, A440–A441 (2004). This abstract introduced the concept of the use-dependent expression of 5-HT 1D receptors.

    Google Scholar 

  113. Pregenzer, J. F., Alberts, G. L., Block, J. H., Slightom, J. L. & Im, W. B. Characterisation of ligand binding properties of the 5-HT1D receptors cloned from chimpanzee, gorilla and rhesus monkey in comparison with those from the human and guinea pig receptors. Neurosci. Lett. 235, 117–120 (1997).

    CAS  PubMed  Google Scholar 

  114. Gomez-Mancilla, B. et al. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia 21, 727–732 (2001).

    CAS  PubMed  Google Scholar 

  115. Pregenzer, J. F. et al. Differential pharmacology between the guinea-pig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands). Br. J. Pharmacol. 127, 468–472 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Fleishaker, J. C. et al. Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU- 142633F. Int. J. Clin. Pharmacol. Ther. 37, 487–492 (1999).

    CAS  PubMed  Google Scholar 

  117. Clements, J. R., Magnusson, K. R., Hautman, J. & Beitz, A. J. Rat tooth pulp projections to spinal trigeminal subnucleus caudalis are glutamate-like immunoreactive. J. Comp. Neurol. 309, 281–288 (1991).

    CAS  PubMed  Google Scholar 

  118. Magnusson, K. R., Larson, A. A., Madl, J. E., Altschuler, R. A. & Beitz, A. J. Co-localization of fixative-modified glutamate and glutaminase in neurons of the spinal trigeminal nucleus of the rat: an immunohistochemical and immunoradiochemical analysis. J. Comp. Neurol. 247, 477–490 (1986).

    CAS  PubMed  Google Scholar 

  119. Tallaksen-Greene, S. J., Young, A. B., Penney, J. B. & Beitz, A. J. Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci. Lett. 141, 79–83 (1992).

    CAS  PubMed  Google Scholar 

  120. Storer, R. J. & Goadsby, P. J. Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. Neuroscience 90, 1371–1376 (1999).

    CAS  PubMed  Google Scholar 

  121. Goadsby, P. J. & Classey, J. D. Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res. 875, 119–124 (2000).

    CAS  PubMed  Google Scholar 

  122. Classey, J. D., Knight, Y. E. & Goadsby, P. J. The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res. 907, 117–124 (2001).

    CAS  PubMed  Google Scholar 

  123. Mitsikostas, D. D., Sanchez del Rio, M., Waeber, C., Moskowitz, M. A. & Cutrer, F. M. The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 76, 239–248 (1998).

    CAS  PubMed  Google Scholar 

  124. Mitsikostas, D. D. et al. Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br. J. Pharmacol. 127, 623–630 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Shields, K. G., Kaube, H. & Goadsby, P. J. GABA receptors modulate trigeminovascular nociceptive transmission in the ventroposteromedial (VPM) thalamic nucleus of the rat. Cephalalgia 23, 728 (2003).

    Google Scholar 

  126. Shields, K. G. & Goadsby, P. J. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine? Brain 128, 86–97 (2005). This is an important description of the possible locus of action of the preventive propranolol in the thalamus.

    PubMed  Google Scholar 

  127. Ramadan, N. M. et al. IV LY293558, an AMPA/kainate receptor antagonist, is effective in migraine. Cephalalgia 21, 267–268 (2001).

    Google Scholar 

  128. Kaube, H., Herzog, J., Kaufer, T., Dichgans, M. & Diener, H. C. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 55, 139–141 (2000).

    CAS  PubMed  Google Scholar 

  129. Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J. & Uddman, R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J. Cereb. Blood Flow Metab. 7, 720–728 (1987).

    CAS  PubMed  Google Scholar 

  130. Goadsby, P. J., Edvinsson, L. & Ekman, R. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann. Neurol. 23, 193–196 (1988).

    CAS  PubMed  Google Scholar 

  131. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990). This was the first description of CGRP and not substance-P release in migraine.

    CAS  PubMed  Google Scholar 

  132. Gallai, V. et al. Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15, 384–390 (1995).

    CAS  PubMed  Google Scholar 

  133. Goadsby, P. J. & Edvinsson, L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain 117, 427–434 (1994). This was the first description of CGRP release in cluster headache.

    PubMed  Google Scholar 

  134. Fanciullacci, M., Alessandri, M., Figini, M., Geppetti, P. & Michelacci, S. Increase in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 60, 119–123 (1995).

    CAS  PubMed  Google Scholar 

  135. Thomsen, L. L., Kruuse, C., Iversen, H. K. & Olesen, J. A nitric oxide donor (nitroglycerine) triggers genuine migraine attacks. Eur. J. Neurol. 1, 73–80 (1994).

    CAS  PubMed  Google Scholar 

  136. Afridi, S., Kaube, H. & Goadsby, P. J. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 110, 675–680 (2004).

    CAS  PubMed  Google Scholar 

  137. Juhasz, G. et al. NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 106, 461–470 (2003).

    CAS  PubMed  Google Scholar 

  138. Buzzi, M. G., Moskowitz, M. A., Shimizu, T. & Heath, H. H. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology 30, 1193–1200 (1991).

    CAS  PubMed  Google Scholar 

  139. Arvieu, L. et al. Sumatriptan inhibits the release of CGRP and substance P from the rat spinal cord. Neuroreport 7, 1973–1976 (1996).

    CAS  PubMed  Google Scholar 

  140. Goadsby, P. J. & Edvinsson, L. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache 34, 394–399 (1994).

    CAS  PubMed  Google Scholar 

  141. Goadsby, P. J. & Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 (1993). This report showed that sumatriptan administration blocked CGRP release in migraine.

    CAS  PubMed  Google Scholar 

  142. Zagami, A. S., Goadsby, P. J. & Edvinsson, L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 16, 69–75 (1990).

    CAS  PubMed  Google Scholar 

  143. Knight, Y. E., Edvinsson, L. & Goadsby, P. J. Blockade of CGRP release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122, 288. Neuropeptides 33, 41–46 (1999).

    CAS  PubMed  Google Scholar 

  144. Knight, Y. E., Edvinsson, L. & Goadsby, P. J. 4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT1B/1D receptor agonist activity. Neuropharmacology 40, 520–525 (2001).

    CAS  PubMed  Google Scholar 

  145. Durham, P. L., Sharma, R. V. & Russo, A. F. Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J. Neurosci. 17, 9545–9553 (1997).

    CAS  PubMed  Google Scholar 

  146. Durham, P. L. & Russo, A. F. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J. Neurosci. 19, 3423–3429 (1999).

    CAS  PubMed  Google Scholar 

  147. Doods, H. et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol. 129, 420–423 (2000). This was the first description of a selective CGRP antagonist.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Moreno, M. J., Abounader, R., Hebert, E., Doods, H. & Hamel, E. Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Neuropharmacology 42, 568–576 (2002).

    CAS  PubMed  Google Scholar 

  149. Petersen, K. A., Lassen, L. H., Birk, S. & Olesen, J. The effect of the nonpeptide CGRP-antagonist, BIBN406BS on human-αCGRP induced headache and hemodynamics in healthy volunteers. Cephalalgia 23, 725 (2003).

    Google Scholar 

  150. Storer, R. J., Akerman, S. & Goadsby, P. J. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br. J. Pharmacol. 142, 1171–1181 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Olesen, J. et al. Calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS is effective in the treatment of migraine attacks. New Eng. J. Med. 350, 1104–1110 (2004). This proof-of-concept study showed that a CGRP antagonist could abort acute migraine.

    CAS  PubMed  Google Scholar 

  152. Petersen, K. A. et al. The novel CGRP-antagonist, BIBN4096BS does not affect the cerebral hemodynamics in healthy volunteers. Cephalalgia 23, 729 (2003).

    Google Scholar 

  153. Sawynok, J. Adenosine receptor activation and nociception. Eur. J. Pharmacol. 347, 1–11 (1998).

    CAS  PubMed  Google Scholar 

  154. Sawynok, J. Purines in pain management. Curr. Opin. Cent. Peripher. Nerv. Syst. Investig. Drugs 1, 27–38 (1999).

    CAS  Google Scholar 

  155. Paalzow, G. & Paalzow, L. The effects of caffeine and theophylline on nociceptive stimulation in the rat. Acta Pharmacol. Toxicol. 32, 22–32 (1973).

    CAS  Google Scholar 

  156. Sawynok, J., Sweeney, M. I. & White, T. D. Classification of adenosine receptors mediating antinociception in the rat spinal cord. Br. J. Pharmacol. 88, 923–930 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Sjolund, K.-F., Sollevi, A., Segerdahl, M., Hansson, P. & Lundeberg, T. Intrathecal and systemic R-phenylisopropy-adenosine reduces scratching behaviour in a rat mononeuropathy model. NeuroReport 7, 1856–1860 (1996).

    CAS  PubMed  Google Scholar 

  158. DeLander, G. E. & Hopkins, G. J. Spinal adenosine modulates descending antinociceptive pathways stimulated by morphine. J. Pharmacol. Exp. Therap. 239, 88–93 (1986).

    CAS  Google Scholar 

  159. DeLander, G. E. & Hopkins, C. J. Interdependence of spinal adenosinergic, serotonergic and noradrenergic systems mediating antinociception. Neuropharmacology 26, 1791–1794 (1987).

    CAS  PubMed  Google Scholar 

  160. Schindler, M., Harris, C. A., Hayes, B., Papotti, M. & Humphrey, P. P. A. Immunohistochemical localization of adenosine A1 receptors in human brain regions. Neurosci. Lett. 297, 211–215 (2001).

    CAS  PubMed  Google Scholar 

  161. Gurden, M. F. et al. Functional characterisation of three adenosine receptor types. Br. J. Pharmacol. 109, 693–698 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Sheehan, M. J., Wilson, D. J., Cousins, R. & Giles, H. Relative intrinsic efficacy of adenosine A1 receptor agonists measured using functional and radioligand binding. Br. J. Pharmacol. 131, 34P (2000).

    Google Scholar 

  163. Goadsby, P. J., Hoskin, K. L., Storer, R. J., Edvinsson, L. & Connor, H. E. Adenosine (A1) receptor agonists inhibit trigeminovascular nociceptive transmission. Brain 125, 1392–1401 (2002). This pivotal paper established an adenosine A 1 receptor agonist as a target for acute migraine therapy.

    CAS  PubMed  Google Scholar 

  164. Santicioli, P., Delbianco, E. & Maggi, C. A. Adenosine A1 receptors mediate the presynaptic inhibition of calcitonin gene related peptide release by adenosine in the rat spinal cord. Eur. J. Pharmacol. 231, 139–142 (1993).

    CAS  PubMed  Google Scholar 

  165. Honey, A. C., Bland-Ward, P. A., Connor, H. E., Feniuk, W. & Humphrey, P. P. A. Study of an adenosine A1 receptor agonist on trigeminally evoked dural blood vessel dilation in the anaesthetized rat. Cephalalgia 22, 260–264 (2000).

    Google Scholar 

  166. Kaube, H., Katsarava, Z., Kaufer, T., Diener, H.-C. & Ellrich, J. A new method to increase the nociception specificity of the human blink reflex. Clin. Neurophysiol. 111, 413–416 (2000).

    CAS  PubMed  Google Scholar 

  167. Giffin, N. J. et al. Effect of adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects. Cephalalgia 23, 287–292 (2003).

    CAS  PubMed  Google Scholar 

  168. Humphrey, P. P. et al. Inhibition of trigeminal nociceptive afferents by adenosine A1 receptor activation: a novel approach towards the design of new anti-migraine compounds. Cephalalgia 21, 268–269 (2001).

    Google Scholar 

  169. Meunier, J., Mouledous, L. & Topham, C. M. The nociceptin (ORL1) receptor: molecular cloning and functional architecture. Peptides 21, 893–900 (2000).

    CAS  PubMed  Google Scholar 

  170. Reinscheid, R. K., Nothacker, H. & Civelli, O. The orphanin FQ/nociceptin gene: structure, tissue distribution of expression and functional implications obtained from knockout mice. Peptides 21, 901–906 (2000).

    CAS  PubMed  Google Scholar 

  171. Mogil, J. S. & Pasternak, G. W. The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol. Rev. 53, 381–415 (2001).

    CAS  PubMed  Google Scholar 

  172. Reinscheid, R. K. et al. Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science 270, 792–794 (1995).

    CAS  Google Scholar 

  173. Darland, T. & Grandy, D. K. The orphanin FQ system: an emerging target for the management of pain? Br. J. Anaesth. 81, 29–37 (1998).

    CAS  PubMed  Google Scholar 

  174. Hou, M., Tajti, J., Uddman, R. & Edvinsson, L. Demonstration of nociceptin positive cells and opioid-receptor like-1 in human trigeminal ganglion. Cephalalgia 21, 402 (2001).

    Google Scholar 

  175. Williamson, D. J., Hargreaves, R. J., Hill, R. G. & Shepheard, S. L. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural blood vessel diameter in the anaesthetized rat. Cephalalgia 17, 518–524 (1997).

    CAS  PubMed  Google Scholar 

  176. Bartsch, T., Akerman, S. & Goadsby, P. J. The ORL-1 (NOP1) receptor ligand nociceptin/orphanin FQ (N/OFQ) inhibits neurogenic vasodilatation in the rat. Neuropharmacology 43, 991–998 (2002).

    CAS  PubMed  Google Scholar 

  177. Okuda-Ashitaka, E. et al. Nocistatin, a peptide that blocks nociceptin action in pain transmission. Nature 392, 286–289 (1998).

    CAS  PubMed  Google Scholar 

  178. Okuda-Ashitaka, E. & Ito, S. Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor. Peptides 21, 1101–1109 (2000).

    CAS  PubMed  Google Scholar 

  179. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    CAS  Google Scholar 

  180. Joo, F., Szolcsanyi, J. & Jancso-Gabor, A. Mitochondrial alterations in the spinal ganglion cells of the rat accompanying the long-lasting sensory disturbance induced by capsaicin. Life Sci. 8, 621–626 (1969).

    CAS  PubMed  Google Scholar 

  181. Guo, A., Vulchanova, L., Wang, J., Li, X. & Elde, R. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur. J. Neurosci. 11, 946–958 (1999).

    CAS  PubMed  Google Scholar 

  182. Ichikawa, H. & Sugimoto, T. VR1-immunoreactive primary sensory neurons in the rat trigeminal ganglion. Brain Res. 890, 184–188 (2001).

    CAS  PubMed  Google Scholar 

  183. Hou, M., Uddman, R., Tajti, J., Kanje, M. & Edvinsson, L. Capsaicin receptor immunoreactivity in the human trigeminal ganglion. Neurosci. Lett. 330, 223–226 (2002).

    CAS  PubMed  Google Scholar 

  184. Akerman, S., Kaube, H. & Goadsby, P. J. Vanilloid type 1 receptor (VR1) evoked CGRP release plays a minor role in causing dural vessel dilation via the trigeminovascular system. Br. J. Pharmacol. 140, 718–724 (2003).

    CAS  PubMed  Google Scholar 

  185. Shepheard, S. L., Williamson, D. J., Beer, M. S., Hill, R. G. & Hargreaves, R. J. Differential effects of 5-HT1B/1D receptor agonists on neurogenic dural plasma extravasation and vasodilation in anaesthetized rats. Neuropharmacology 36, 525–533 (1997).

    Google Scholar 

  186. Williamson, D. J., Shepheard, S. L., Hill, R. G. & Hargreaves, R. J. The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur. J. Pharmacol. 328, 61–64 (1997).

    CAS  PubMed  Google Scholar 

  187. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    CAS  PubMed  Google Scholar 

  188. Hoehe, M. R. et al. Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14-q15. New Biol. 3, 880–885 (1991).

    CAS  PubMed  Google Scholar 

  189. Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    CAS  PubMed  Google Scholar 

  190. Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

    CAS  PubMed  Google Scholar 

  191. Dewey, W. L. Cannabinoid pharmacology. Pharmacol. Rev. 38, 151–178 (1986).

    CAS  PubMed  Google Scholar 

  192. Smith, P. B. et al. The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. J. Pharmacol. Exp. Ther. 270, 219–227 (1994).

    PubMed  Google Scholar 

  193. Adams, I. B., Compton, D. R. & Martin, B. R. Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J. Pharmacol. Exp. Ther. 284, 1209–1217 (1998).

    CAS  PubMed  Google Scholar 

  194. Crawley, J. N. et al. Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol. Biochem. Behav. 46, 967–972 (1993).

    CAS  PubMed  Google Scholar 

  195. Akerman, S., Kaube, H. & Goadsby, P. J. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J. Pharmacol. Exp. Ther. 309, 56–63 (2004). This important paper established CB 1 receptor targets in the trigeminovascular system.

    CAS  PubMed  Google Scholar 

  196. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999).

    CAS  PubMed  Google Scholar 

  197. Akerman, S., Kaube, H. & Goadsby, P. J. Anandamide shows both cannabinoid and vanilloid properties in an in vivo model of trigeminovascular mediated headpain. Cephalalgia 23, 646 (2003).

    Google Scholar 

  198. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 696–697 (1998).

    Google Scholar 

  199. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).

    CAS  PubMed  Google Scholar 

  200. Trivedi, P., Yu, H., MacNeil, D. J., Van der Ploeg, L. H. & Guan, X. M. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75 (1998).

    CAS  PubMed  Google Scholar 

  201. Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998).

    CAS  PubMed  Google Scholar 

  202. Marcus, J. N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001).

    CAS  PubMed  Google Scholar 

  203. Date, Y. et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc. Natl Acad. Sci. USA 96, 748–753 (1999).

    CAS  PubMed  Google Scholar 

  204. Nambu, T. et al. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260 (1999).

    CAS  PubMed  Google Scholar 

  205. Smart, D. & Jerman, J. The physiology and pharmacology of the orexins. Pharmacol. Ther. 94, 51 (2002). An excellent review on orexins.

    CAS  PubMed  Google Scholar 

  206. van den Pol, A. N., Gao, X. B., Obrietan, K., Kilduff, T. S. & Belousov, A. B. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J. Neurosci. 18, 7962–7971 (1998).

    CAS  PubMed  Google Scholar 

  207. Siegel, J. M. Narcolepsy: a key role for hypocretins (orexins). Cell 98, 409–412 (1999).

    CAS  PubMed  Google Scholar 

  208. Bingham, S. et al. Orexin-A, an hypothalamic peptide with analgesic properties. Pain 92, 81–90 (2001).

    CAS  PubMed  Google Scholar 

  209. Yamamoto, T., Nozaki-Taguchi, N. & Chiba, T. Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. Br. J. Pharmacol. 137, 170–176 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Grudt, T. J., van den Pol, A. N. & Perl, E. R. Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat. J. Physiol. 538, 517–525 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Benjamin, L. et al. Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol. Dis. 16, 500–505 (2004).

    CAS  PubMed  Google Scholar 

  212. Bartsch, T., Levy, M. J., Knight, Y. E. & Goadsby, P. J. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109, 367–378 (2004). This interesting paper showed the differential effects of orexin A and B in the hypothalamus.

    CAS  PubMed  Google Scholar 

  213. Hagan, J. J. et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc. Natl Acad. Sci. USA 96, 10911–10916 (1999).

    CAS  PubMed  Google Scholar 

  214. Soffin, E. M. et al. SB-334867-A antagonises orexin mediated excitation in the locus coeruleus. Neuropharmacology 42, 127–133 (2002).

    CAS  PubMed  Google Scholar 

  215. Thomsen, L. L. & Olesen, J. Nitric oxide in primary headaches. Curr. Opin. Neurol. 14, 315–321 (2001).

    CAS  PubMed  Google Scholar 

  216. Thomsen, L. L. & Olesen, J. A pivotal role of nitric oxide in migraine pain. Ann. NY Acad. Sci. 835, 363–372 (1997). An excellent review of NO mechanisms in migraine.

    CAS  PubMed  Google Scholar 

  217. Olesen, J., Thomsen, L. L., Lassen, L. H. & Olesen, I. J. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia 15, 94–100 (1995).

    CAS  PubMed  Google Scholar 

  218. Iversen, H. K., Olesen, J. & Tfelt-Hansen, P. Intravenous nitroglycerin as an experimental headache model. Basic characteristics. Pain 38, 17–24 (1989).

    CAS  PubMed  Google Scholar 

  219. Giffin, N. J. et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 60, 935–940 (2003).

    CAS  PubMed  Google Scholar 

  220. Kruuse, C., Thomsen, L. L., Birk, S. & Olesen, J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126, 241–247 (2003).

    PubMed  Google Scholar 

  221. Reuter, U. et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124, 2490–2502 (2001).

    CAS  PubMed  Google Scholar 

  222. Hoskin, K. L., Bulmer, D. C. E. & Goadsby, P. J. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci. Lett. 266, 173–176 (1999).

    CAS  PubMed  Google Scholar 

  223. Lipton, R. B., Diamond, S., Reed, M., Diamond, M. L. & Stewart, W. F. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 41, 638–645 (2001).

    CAS  PubMed  Google Scholar 

  224. Matharu, M. S. et al. Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain 127, 220–230 (2004).

    PubMed  Google Scholar 

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The work of the author is supported by the Wellcome Trust.

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  1. Headache Group, Institute of Neurology, and The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    Peter J. Goadsby

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  1. Peter J. Goadsby
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Competing interests

P.J.G. is a consultant for or has done research with GSK, Pfizer, Astra Zeneca, Allergen, Medtronic, BMS and Boehringer.

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DATABASES

Entrez Gene

CACNA1A

OMIM

cluster headache

familial hemiplegic migraine

migrane with aura

narcolepsy

Glossary

HABITUATION

A reduced response to the same sensory input.

CONTINGENT NEGATIVE VARIATION

A negative wave that is associated with an anticipatory stimulus.

CORTICAL SPREADING DEPRESSION

A wave of neuronal activation followed by inhibition that moves across the cortex at a characteristically slow rate of 3–6 mm per min.

TRIGEMINAL BLINK REFLEX

The response of the muscles around the eye to an electrical stimulus that causes them to close (blink), which can be measured using recording electrodes.

INTRAVITAL MODEL OF WILLIAMS AND HARGREAVES

An experimental animal system in which vessels in the rat dura mater can be directly studied by measuring their diameter in response to stimuli.

ALLODYNIA

Pain from non-noxious heat, cold or pressure.

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Goadsby, P. Can we Develop Neurally Acting Drugs for the Treatment of Migraine?. Nat Rev Drug Discov 4, 741–750 (2005). https://doi.org/10.1038/nrd1822

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