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Migraine: where and how does the pain originate?

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Abstract

Migraine is a complex neurological disease with a genetic background. Headache is the most prominent and clinically important symptom of migraine but its origin is still enigmatic. Numerous clinical, histochemical, electrophysiological, molecular and genetical approaches form a puzzle of findings that slowly takes shape. The generation of primary headaches like migraine pain seems to be the consequence of multiple pathophysiological changes in meningeal tissues, the trigeminal ganglion, trigeminal brainstem nuclei and descending inhibitory systems, based on specific characteristics of the trigeminovascular system. This contribution reviews the current discussion of where and how the migraine pain may originate and outlines the experimental work to answer these questions.

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References

  • Acosta MC, Belmonte C, Gallar J (2001) Sensory experiences in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea. J Physiol 534:511–525

    Article  PubMed  CAS  Google Scholar 

  • Afridi SK, Giffin NJ, Kaube H, Friston KJ, Ward NS, Frackowiak RS, Goadsby PJ (2005a) A positron emission tomographic study in spontaneous migraine. Arch Neurol 62:1270–1275

    Article  PubMed  Google Scholar 

  • Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, Goadsby PJ (2005b) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128:932–939

    Article  PubMed  CAS  Google Scholar 

  • Aimar P, Pasti L, Carmignoto G, Merighi A (1998) Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J Neurosci 18:10375–10388

    PubMed  CAS  Google Scholar 

  • Akerman S, Williamson DJ, Kaube H, Goadsby PJ (2002) The role of histamine in dural vessel dilation. Brain Res 956:96–102

    Article  PubMed  CAS  Google Scholar 

  • Andres KH, Von During M, Muszynski K, Schmidt RF (1987) Nerve fibres and their terminals of the dura mater encephali of the rat. Anat Embryol (Berl) 175:289–301

    Article  CAS  Google Scholar 

  • Arulmani U, Maassenvandenbrink A, Villalon CM, Saxena PR (2004) Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500:315–330

    Article  PubMed  CAS  Google Scholar 

  • Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J (2000) Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 86:133–138

    Article  PubMed  CAS  Google Scholar 

  • Ashkenazi A, Young WB (2005) The effects of greater occipital nerve block and trigger point injection on brush allodynia and pain in migraine. Headache 45:350–354

    Article  PubMed  Google Scholar 

  • Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA (2006) Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol 59:652–661

    Article  PubMed  CAS  Google Scholar 

  • Bartsch T, Goadsby PJ (2002) Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain 125:1496–1509

    Article  PubMed  Google Scholar 

  • Bellamy J, Bowen EJ, Russo AF, Durham PL (2006a) Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci 23:2057–2066

    Article  PubMed  Google Scholar 

  • Bellamy JL, Cady RK, Durham PL (2006b) Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache 46:24–33

    Article  PubMed  Google Scholar 

  • Belmonte C, Giraldez F (1981) Responses of cat corneal sensory receptors to mechanical and thermal stimulation. J Physiol 321:355–368

    PubMed  CAS  Google Scholar 

  • Blau JN (1992) Migraine: theories of pathogenesis. Lancet 339:1202–1207

    Article  PubMed  CAS  Google Scholar 

  • Blau JN, Dexter SL (1981) The site of pain origin during migraine attacks. Cephalalgia 1:143–147

    Article  PubMed  CAS  Google Scholar 

  • Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA (2002) Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8:136–142

    Article  PubMed  CAS  Google Scholar 

  • Bove GM, Moskowitz MA (1997) Primary afferent neurons innervating guinea pig dura. J Neurophysiol 77:299–308

    PubMed  CAS  Google Scholar 

  • Buki A, Horvath Z, Kallo I, Liposits Z, Lengvari I, Doczi TP (1999) Peptidergic innervation of human cerebral blood vessels and saccular aneurysms. Acta Neuropathol 98:383–388

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Burstein R, Yamamura H, Malick A, Strassman AM (1998) Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 79:964–982

    PubMed  CAS  Google Scholar 

  • Burstein R, Levy D, Jakubowski M (2005) Effects of sensitization of trigeminovascular neurons to triptan therapy during migraine. Rev Neurol (Paris) 161:658–660

    CAS  Google Scholar 

  • Burstein R, Levy D, Jakubowski M, Woolf CJ (2006) Peripheral and central sensitization related to headaches. In: Olesen J, Goadsby PJ, Ramadan NB, Tfelt-Hansen P, Welch KMA (eds) The headaches, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 121–129

    Google Scholar 

  • Buzzi MG, Moskowitz MA (1991) Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia 11:165–168

    Article  PubMed  CAS  Google Scholar 

  • Buzzi MG, Moskowitz MA (1992) The trigemino-vascular system and migraine. Pathol Biol (Paris) 40:313–317

    CAS  Google Scholar 

  • Buzzi MG, Bonamini M, Moskowitz MA (1995) Neurogenic model of migraine. Cephalalgia 15:277–280

    Article  PubMed  CAS  Google Scholar 

  • Chiang CY, Hu JW, Sessle BJ (1994) Parabrachial area and nucleus raphe magnus-induced modulation of nociceptive and nonnociceptive trigeminal subnucleus caudalis neurons activated by cutaneous or deep inputs. J Neurophysiol 71:2430–2445

    PubMed  CAS  Google Scholar 

  • Christiansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J (1999) Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 19:660–667

    Article  PubMed  CAS  Google Scholar 

  • Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30

    Article  PubMed  CAS  Google Scholar 

  • D’Amico D, Ferraris A, Leone M, Catania A, Carlin A, Grazzi L, Bussone G (2002) Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine-NO pathway? Cephalalgia 22:33–36

    Article  PubMed  Google Scholar 

  • Davis KD, Dostrovsky JO (1986) Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation. Pain 25:395–401

    Article  PubMed  CAS  Google Scholar 

  • Davis KD, Dostrovsky JO (1988a) Cerebrovascular application of bradykinin excites central sensory neurons. Brain Res 446:401–406

    Article  PubMed  CAS  Google Scholar 

  • Davis KD, Dostrovsky JO (1988b) Responses of feline trigeminal spinal tract nucleus neurons to stimulation of the middle meningeal artery and sagittal sinus. J Neurophysiol 59:648–666

    PubMed  CAS  Google Scholar 

  • De Col R, Koulchitsky SV, Messlinger KB (2003) Nitric oxide synthase inhibition lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus. Neuroreport 14:229–232

    Article  PubMed  Google Scholar 

  • Dodick D, Silberstein S (2006) Central sensitization theory of migraine: clinical implications. Headache 46(Suppl 4):S182–S191

    Article  PubMed  Google Scholar 

  • Dostrovsky JO, Davis KD, Kawakita K (1991) Central mechanisms of vascular headaches. Can J Physiol Pharmacol 69:652–658

    PubMed  CAS  Google Scholar 

  • Drummond PD, Lance JW (1983) Extracranial vascular changes and the source of pain in migraine headache. Ann Neurol 13:32–37

    Article  PubMed  CAS  Google Scholar 

  • Drummond PD, Lance JW (1984) Neurovascular disturbances in headache patients. Clin Exp Neurol 20:93–99

    PubMed  CAS  Google Scholar 

  • Dux M, Schwenger N, Messlinger K (2002) Possible role of histamine (H1- and H2-) receptors in the regulation of meningeal blood flow. Br J Pharmacol 137:874–880

    Article  PubMed  CAS  Google Scholar 

  • Dux M, Santha P, Jancso G (2003) Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat. J Physiol 552:859–867

    Article  PubMed  CAS  Google Scholar 

  • Eberhardt M, Hoffmann T, Sauer SK, Messlinger K, Reeh PW, Fischer MJ (2008) Calcitonin gene-related peptide release from intact isolated dorsal root and trigeminal ganglia. Neuropeptides 42:311–317

    Article  PubMed  CAS  Google Scholar 

  • Ebersberger A, Ringkamp M, Reeh PW, Handwerker HO (1997) Recordings from brain stem neurons responding to chemical stimulation of the subarachnoid space. J Neurophysiol 77:3122–3133

    PubMed  CAS  Google Scholar 

  • Ebersberger A, Averbeck B, Messlinger K, Reeh PW (1999a) Release of substance P, calcitonin gene-related peptide and prostaglandin E2 from rat dura mater encephali following electrical and chemical stimulation in vitro. Neuroscience 89:901–907

    Article  PubMed  CAS  Google Scholar 

  • Ebersberger A, Handwerker HO, Reeh PW (1999b) Nociceptive neurons in the rat caudal trigeminal nucleus respond to blood plasma perfusion of the subarachnoid space: the involvement of complement. Pain 81:283–288

    Article  PubMed  CAS  Google Scholar 

  • Ebersberger A, Schaible HG, Averbeck B, Richter F (2001) Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache? Ann Neurol 49:7–13

    Article  PubMed  CAS  Google Scholar 

  • Edvinsson L, Uddman R (1981) Adrenergic, cholinergic and peptidergic nerve fibres in dura mater-involvement in headache? Cephalalgia 1:175–179

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ellrich J, Messlinger K (1999) Afferent input to the medullary dorsal horn from the contralateral face in rat. Brain Res 826:321–324

    Article  PubMed  CAS  Google Scholar 

  • Ellrich J, Andersen OK, Messlinger K, Arendt-Nielsen L (1999a) Convergence of meningeal and facial afferents onto trigeminal brainstem neurons: an electrophysiological study in rat and man. Pain 82:229–237

    Article  PubMed  CAS  Google Scholar 

  • Ellrich J, Schepelmann K, Pawlak M, Messlinger K (1999b) Acetylsalicylic acid inhibits meningeal nociception in rat. Pain 81:7–14

    Article  PubMed  CAS  Google Scholar 

  • Ellrich J, Messlinger K, Chiang CY, Hu JW (2001) Modulation of neuronal activity in the nucleus raphe magnus by the 5-HT(1)-receptor agonist naratriptan in rat. Pain 90:227–231

    Article  PubMed  CAS  Google Scholar 

  • Eltorp CT, Jansen-Olesen I, Hansen AJ (2000) Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide. Cephalalgia 20:838–844

    Article  PubMed  CAS  Google Scholar 

  • Escott KJ, Beattie DT, Connor HE, Brain SD (1995) Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide. Brain Res 669:93–99

    Article  PubMed  CAS  Google Scholar 

  • Feindel W, Penfield W, McNaughton F (1960) The tentorial nerves and localization of intracranial pain in man. Neurology 10:555–563

    PubMed  CAS  Google Scholar 

  • Fields HL (2000) Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 122:245–253

    Article  PubMed  CAS  Google Scholar 

  • Fischer MJ, Koulchitsky S, Messlinger K (2005) The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci 25:5877–5883

    Article  PubMed  CAS  Google Scholar 

  • Flores CM, Leong AS, Dussor GO, Harding-Rose C, Hargreaves KM, Kilo S (2001) Capsaicin-evoked CGRP release from rat buccal mucosa: development of a model system for studying trigeminal mechanisms of neurogenic inflammation. Eur J Neurosci 14:1113–1120

    Article  PubMed  CAS  Google Scholar 

  • Fricke B, Andres KH, Von During M (2001) Nerve fibers innervating the cranial and spinal meninges: morphology of nerve fiber terminals and their structural integration. Microsc Res Tech 53:96–105

    Article  PubMed  CAS  Google Scholar 

  • Garry MG, Richardson JD, Hargreaves KM (1994) Sodium nitroprusside evokes the release of immunoreactive calcitonin gene-related peptide and substance P from dorsal horn slices via nitric oxide-dependent and nitric oxide-independent mechanisms. J Neurosci 14:4329–4337

    PubMed  CAS  Google Scholar 

  • Gazerani P, Pourpak Z, Ahmadiani A, Hemmati A, Kazemnejad A (2003) A correlation between migraine, histamine and immunoglobulin E. Iran J Allergy Asthma Immunol 2:17–24

    PubMed  CAS  Google Scholar 

  • Goadsby PJ, Lambert GA, Lance JW (1982) Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res 249:247–254

    Article  PubMed  CAS  Google Scholar 

  • Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23:193–196

    Article  PubMed  CAS  Google Scholar 

  • Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28:183–187

    Article  PubMed  CAS  Google Scholar 

  • Greco R, Tassorelli C, Cappelletti D, Sandrini G, Nappi G (2005) Activation of the transcription factor NF-kappaB in the nucleus trigeminalis caudalis in an animal model of migraine. Neurotoxicology 26:795–800

    Article  PubMed  CAS  Google Scholar 

  • Hadjikhani N, Sanchez DR, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 98:4687–4692

    Article  PubMed  CAS  Google Scholar 

  • Haimart M, Pradalier A, Launay JM, Dreux C, Dry J (1987) Whole blood and plasma histamine in common migraine. Cephalalgia 7:39–42

    Article  PubMed  CAS  Google Scholar 

  • Hayashi H, Sumino R, Sessle BJ (1984) Functional organization of trigeminal subnucleus interpolaris: nociceptive and innocuous afferent inputs, projections to thalamus, cerebellum, and spinal cord, and descending modulation from periaqueductal gray. J Neurophysiol 51:890–905

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312

    Article  PubMed  CAS  Google Scholar 

  • Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30:5–11

    PubMed  CAS  Google Scholar 

  • Hoskin KL, Zagami AS, Goadsby PJ (1999) Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat 194(Pt 4):579–588

    Article  PubMed  CAS  Google Scholar 

  • Ingvar M (1999) Pain and functional imaging. Philos Trans R Soc Lond B Biol Sci 354:1347–1358

    Article  PubMed  CAS  Google Scholar 

  • Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ (1997) Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression. Pain 72:407–415

    Article  PubMed  CAS  Google Scholar 

  • Iversen HK (1995) Experimental headache in humans. Cephalalgia 15:281–287

    Article  PubMed  CAS  Google Scholar 

  • Jakubowski M, Levy D, Goor-Aryeh I, Collins B, Bajwa Z, Burstein R (2005) Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors. Headache 45:850–861

    Article  PubMed  Google Scholar 

  • Jansen SC, van Dusseldorp M, Bottema KC, Dubois AE (2003) Intolerance to dietary biogenic amines: a review. Ann Allergy Asthma Immunol 91:233–240

    Article  PubMed  CAS  Google Scholar 

  • Jansen-Olesen I, Mortensen A, Edvinsson L (1996) Calcitonin gene-related peptide is released from capsaicin-sensitive nerve fibres and induces vasodilatation of human cerebral arteries concomitant with activation of adenylyl cyclase. Cephalalgia 16:310–316

    Article  PubMed  CAS  Google Scholar 

  • Jenkins DW, Langmead CJ, Parsons AA, Strijbos PJ (2004) Regulation of calcitonin gene-related peptide release from rat trigeminal nucleus caudalis slices in vitro. Neurosci Lett 366:241–244

    Article  PubMed  CAS  Google Scholar 

  • Jensen K (1993) Extracranial blood flow, pain and tenderness in migraine clinical and experimental studies. Acta Neurol Scand Suppl 147:1–27

    PubMed  CAS  Google Scholar 

  • Jensen R (2000) Central and peripheral mechanisms in migraine: a neurophysiological approach. Funct Neurol 15(Suppl 3):63–67

    PubMed  Google Scholar 

  • Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J, Szolcsanyi J, Vitrai J, Bagdy G (2003) 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

    Article  PubMed  CAS  Google Scholar 

  • Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G (2005) Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 25:179–183

    Article  PubMed  CAS  Google Scholar 

  • Kashiba H, Fukui H, Morikawa Y, Senba E (1999) Gene expression of histamine H1 receptor in guinea pig primary sensory neurons: a relationship between H1 receptor mRNA-expressing neurons and peptidergic neurons. Brain Res Mol Brain Res 66:24–34

    Article  PubMed  CAS  Google Scholar 

  • Kashiba H, Fukui H, Senba E (2001) Histamine H1 receptor mRNA is expressed in capsaicin-insensitive sensory neurons with neuropeptide Y-immunoreactivity in guinea pigs. Brain Res 901:85–93

    Article  PubMed  CAS  Google Scholar 

  • Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ (1993) Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res 629:95–102

    Article  PubMed  CAS  Google Scholar 

  • Keller JT, Marfurt CF (1991) Peptidergic and serotoninergic innervation of the rat dura mater. J Comp Neurol 309:515–534

    Article  PubMed  CAS  Google Scholar 

  • Keller JT, Saunders MC, Beduk A, Jollis JG (1985) Innervation of the posterior fossa dura of the cat. Brain Res Bull 14:97–102

    Article  PubMed  CAS  Google Scholar 

  • Kelman L (2004) The aura: a tertiary care study of 952 migraine patients. Cephalalgia 24:728–734

    Article  PubMed  CAS  Google Scholar 

  • Kelman L (2005) Migraine pain location: a tertiary care study of 1283 migraineurs. Headache 45:1038–1047

    Article  PubMed  Google Scholar 

  • Knight YE, Goadsby PJ (2001) The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience 106:793–800

    Article  PubMed  CAS  Google Scholar 

  • Knight YE, Bartsch T, Kaube H, Goadsby PJ (2002) P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 22:RC213

    PubMed  Google Scholar 

  • Knyihar-Csillik E, Vecsei L (1999) Effect of a nitric oxide donor on nitroxergic nerve fibers in the rat dura mater. Neurosci Lett 260:97–100

    Article  PubMed  CAS  Google Scholar 

  • Koulchitsky S, Fischer MJ, De Col R, Schlechtweg PM, Messlinger K (2004) Biphasic response to nitric oxide of spinal trigeminal neurons with meningeal input in rat-possible implications for the pathophysiology of headaches. J Neurophysiol 92:1320–1328

    Article  PubMed  CAS  Google Scholar 

  • Koulchitsky S, Fischer MJM, Messlinger K (2009) Calcitonin gene-related peptide receptor inhibition reduces neuronal activity induced by prolonged increase in nitric oxide in the rat spinal trigeminal nucleus. Cephalalgia 29:408–417

    Article  PubMed  CAS  Google Scholar 

  • Krabbe AA, Olesen J (1980) Headache provocation by continuous intravenous infusion of histamine Clinical results and receptor mechanisms. Pain 8:253–259

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Kurosawa M, Messlinger K, Pawlak M, Schmidt RF (1995) Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide. Br J Pharmacol 114:1397–1402

    PubMed  CAS  Google Scholar 

  • Lance JW (1981) Headache. Ann Neurol 10:1–10

    Article  PubMed  CAS  Google Scholar 

  • Lassen LH, Heinig JH, Oestergaard S, Olesen J (1996a) Histamine inhalation is a specific but insensitive laboratory test for migraine. Cephalalgia 16:550–553

    Article  PubMed  CAS  Google Scholar 

  • Lassen LH, Thomsen LL, Kruuse C, Iversen HK, Olesen J (1996b) Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine support for the NO-hypothesis of migraine. Eur J Clin Pharmacol 49:335–339

    Article  PubMed  CAS  Google Scholar 

  • Lassen LH, Ashina M, Christiansen I, Ulrich V, Grover R, Donaldson J, Olesen J (1998) Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks. Cephalalgia 18:27–32

    Article  PubMed  CAS  Google Scholar 

  • Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalgia 22:54–61

    Article  PubMed  CAS  Google Scholar 

  • Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J, Tfelt-Hansen P (2008) Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain 9:151–157

    Article  PubMed  CAS  Google Scholar 

  • Lauritzen M (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117(Pt 1):199–210

    Article  PubMed  Google Scholar 

  • Lauritzen M (2001) Cortical spreading depression in migraine. Cephalalgia 21:757–760

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, Kawai Y, Shiosaka S, Takami K, Kiyama H, Hillyard CJ, Girgis S, MacIntyre I, Emson PC, Tohyama M (1985) Coexistence of calcitonin gene-related peptide and substance P-like peptide in single cells of the trigeminal ganglion of the rat: immunohistochemical analysis. Brain Res 330:194–196

    Article  PubMed  CAS  Google Scholar 

  • Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, Messlinger K (2008) 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 507:1277–1299

    Article  PubMed  CAS  Google Scholar 

  • Levy D, Strassman AM (2002) Mechanical response properties of A and C primary afferent neurons innervating the rat intracranial dura. J Neurophysiol 88:3021–3031

    Article  PubMed  Google Scholar 

  • Levy D, Strassman AM (2004) Modulation of dural nociceptor mechanosensitivity by the nitric oxide-cyclic GMP signaling cascade. J Neurophysiol 92:766–772

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM (2007) Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 130:166–176

    Article  PubMed  CAS  Google Scholar 

  • Lin Q, Palecek J, Paleckova V, Peng YB, Wu J, Cui M, Willis WD (1999) Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol 81:1075–1085

    PubMed  CAS  Google Scholar 

  • Lipton RB, Bigal ME, Steiner TJ, Silberstein SD, Olesen J (2004) Classification of primary headaches. Neurology 63:427–435

    PubMed  CAS  Google Scholar 

  • Liu Y, Broman J, Edvinsson L (2004) Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience 129:431–437

    Article  PubMed  CAS  Google Scholar 

  • Lovick TA, Wolstencroft JH (1979) Inhibitory effects of nucleus raphe magnus on neuronal responses in the spinal trigeminal nucleus to nociceptive compared with non-nociceptive inputs. Pain 7:135–145

    Article  PubMed  CAS  Google Scholar 

  • Lowman MA, Benyon RC, Church MK (1988) Characterization of neuropeptide-induced histamine release from human dispersed skin mast cells. Br J Pharmacol 95:121–130

    PubMed  CAS  Google Scholar 

  • Marfurt CF (1981) The central projections of trigeminal primary afferent neurons in the cat as determined by the tranganglionic transport of horseradish peroxidase. J Comp Neurol 203:785–798

    Article  PubMed  CAS  Google Scholar 

  • Marfurt CF, Turner DF (1984) The central projections of tooth pulp afferent neurons in the rat as determined by the transganglionic transport of horseradish peroxidase. J Comp Neurol 223:535–547

    Article  PubMed  CAS  Google Scholar 

  • Martin RS, Martin GR (2001) Investigations into migraine pathogenesis: time course for effects of m-CPP, BW723C86 or glyceryl trinitrate on appearance of Fos-like immunoreactivity in rat trigeminal nucleus caudalis (TNC). Cephalalgia 21:46–52

    Article  PubMed  CAS  Google Scholar 

  • Martino G, Perkins MN (2008) Tactile-induced ultrasonic vocalization in the rat: a novel assay to assess anti-migraine therapies in vivo. Cephalalgia 28:723–733

    Article  PubMed  CAS  Google Scholar 

  • Matsubara T, Moskowitz MA, Byun B (1991) CP-93, 129, a potent and selective 5-HT1B receptor agonist blocks neurogenic plasma extravasation within rat but not guinea-pig dura mater. Br J Pharmacol 104:3–4

    PubMed  CAS  Google Scholar 

  • May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19:115–127

    Article  PubMed  CAS  Google Scholar 

  • May A, Goadsby PJ (2001) Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs 10:673–678

    Article  PubMed  CAS  Google Scholar 

  • May A, Kaube H, Buchel C, Eichten C, Rijntjes M, Juptner M, Weiller C, Diener HC (1998) Experimental cranial pain elicited by capsaicin: a PET study. Pain 74:61–66

    Article  PubMed  CAS  Google Scholar 

  • Mayberg M, Langer RS, Zervas NT, Moskowitz MA (1981) Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 213:228–230

    Article  PubMed  CAS  Google Scholar 

  • Mayberg MR, Zervas NT, Moskowitz MA (1984) Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry. J Comp Neurol 223:46–56

    Article  PubMed  CAS  Google Scholar 

  • McNaughton M (1938) The innervation of the intracranial blood vessels and dural sinuses. Assoc Res Nerv Ment Dis 18:178–200

    Google Scholar 

  • Meller ST, Gebhart GF (1993) Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain 52:127–136

    Article  PubMed  CAS  Google Scholar 

  • Meller ST, Cummings CP, Traub RJ, Gebhart GF (1994) The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience 60:367–374

    Article  PubMed  CAS  Google Scholar 

  • Messlinger K, Burstein R (2000) Anatomy of central nervous system pathways related to head pain. In: Olesen J, Tfelt-Hansen P, Welch KMA (eds) The headaches, 2nd edn. Lippincott Williams & Wilkins, Philadelphia, pp 77–86

    Google Scholar 

  • Messlinger K, Pawlak M (1999) Regulation of meningeal blood flow by neuropeptides: relevance to migraine. In: Brain SD, Moore PK (eds) Pain and neurogenic inflammation—progress in inflammation research. Birkhäuser, Basel, pp 245–274

    Google Scholar 

  • Messlinger K, Hanesch U, Baumgartel M, Trost B, Schmidt RF (1993) Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity. Anat Embryol (Berl) 188:219–237

    CAS  Google Scholar 

  • Messlinger K, Dostrovsky JO, Strassman AM (2006) Anatomy and physiology of head pain. In: Olesen J, Goadsby PJ, Ramadan NB, Tfelt-Hansen P, Welch KMA (eds) The headaches, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 95–109

    Google Scholar 

  • Millichap JG, Yee MM (2003) The diet factor in pediatric and adolescent migraine. Pediatr Neurol 28:9–15

    Article  PubMed  Google Scholar 

  • Montagna P (2008) The primary headaches: genetics, epigenetics and a behavioural genetic model. J Headache Pain 9:57–69

    Article  PubMed  Google Scholar 

  • Morgan MM, Fields HL (1994) Pronounced changes in the activity of nociceptive modulatory neurons in the rostral ventromedial medulla in response to prolonged thermal noxious stimuli. J Neurophysiol 72:1161–1170

    PubMed  CAS  Google Scholar 

  • Moskowitz MA (1993) Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 43:S16–S20

    PubMed  CAS  Google Scholar 

  • Multon S, Pardutz A, Mosen J, Hua MT, Defays C, Honda S, Harada N, Bohotin C, Franzen R, Schoenen J (2005) Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice. Pain 114:257–265

    Article  PubMed  CAS  Google Scholar 

  • O’Connor TP, van der Kooy D (1988) Enrichment of a vasoactive neuropeptide (calcitonin gene related peptide) in the trigeminal sensory projection to the intracranial arteries. J Neurosci 8:2468–2476

    PubMed  Google Scholar 

  • Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh-Hofer S, Rohde W, Arnold G, Dirnagl U, Jansen-Olesen I, Reuter U (2005) CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 25:225–236

    Article  PubMed  CAS  Google Scholar 

  • Olesen J, Iversen HK, Thomsen LL (1993) Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 4:1027–1030

    Article  PubMed  CAS  Google Scholar 

  • Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J (2002) Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci 15:1803–1809

    Article  PubMed  CAS  Google Scholar 

  • Pardutz A, Szatmari E, Vecsei L, Schoenen J (2004) Nitroglycerin-induced nNOS increase in rat trigeminal nucleus caudalis is inhibited by systemic administration of lysine acetylsalicylate but not of sumatriptan. Cephalalgia 24:439–445

    Article  PubMed  CAS  Google Scholar 

  • Peatfield RC (1995) Relationships between food, wine, and beer-precipitated migrainous headaches. Headache 35:355–357

    Article  PubMed  CAS  Google Scholar 

  • Piovesan EJ, Kowacs PA, Tatsui CE, Lange MC, Ribas LC, Werneck LC (2001) Referred pain after painful stimulation of the greater occipital nerve in humans: evidence of convergence of cervical afferences on trigeminal nuclei. Cephalalgia 21:107–109

    Article  PubMed  CAS  Google Scholar 

  • Ray BS, Wolff HG (1940) Experimental studies on headache: pain-sensitive structures of the head and their significance in headache. Arch.Surg 41:813–856

    Google Scholar 

  • Reuter U, Sanchez DR, Moskowitz MA (2000) Experimental models of migraine. Funct Neurol 15(Suppl 3):9–18

    PubMed  Google Scholar 

  • Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez dR, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA (2001) Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124:2490–2502

    Article  PubMed  CAS  Google Scholar 

  • Reuter U, Chiarugi A, Bolay H, Moskowitz MA (2002) Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol 51:507–516

    Article  PubMed  CAS  Google Scholar 

  • Reynier-Rebuffel AM, Mathiau P, Callebert J, Dimitriadou V, Farjaudon N, Kacem K, Launay JM, Seylaz J, Abineau P (1994) Substance P, calcitonin gene-related peptide, and capsaicin release serotonin from cerebrovascular mast cells. Am J Physiol 267:R1421–R1429

    PubMed  CAS  Google Scholar 

  • Roch M, Messlinger K, Kulchitsky V, Tichonovich O, Azev O, Koulchitsky S (2007) Ongoing activity in trigeminal wide-dynamic range neurons is driven from the periphery. Neuroscience 150:681–691

    Article  PubMed  CAS  Google Scholar 

  • Rudomin P, Schmidt RF (1999) Presynaptic inhibition in the vertebrate spinal cord revisited. Exp Brain Res 129:1–37

    Article  PubMed  CAS  Google Scholar 

  • Russell MB, Olesen J (1996) A nosographic analysis of the migraine aura in a general population. Brain 119:355–361

    Article  PubMed  Google Scholar 

  • Sandkuhler J (1996) The organization and function of endogenous antinociceptive systems. Prog Neurobiol 50:49–81

    PubMed  CAS  Google Scholar 

  • Sarchielli P, Alberti A, Codini M, Floridi A, Gallai V (2000) Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20:907–918

    Article  PubMed  CAS  Google Scholar 

  • Schepelmann K, Ebersberger A, Pawlak M, Oppmann M, Messlinger K (1997) Activation of trigeminal brain stem neurons by chemical stimulation of the dura mater encephali-preparation for studying meningeal nociception in the rat. Schmerz 11:322–327

    Article  PubMed  CAS  Google Scholar 

  • Schepelmann K, Ebersberger A, Pawlak M, Oppmann M, Messlinger K (1999) Response properties of trigeminal brain stem neurons with input from dura mater encephali in the rat. Neuroscience 90:543–554

    Article  PubMed  CAS  Google Scholar 

  • Schlechtweg PM, Fischer MJM, Messlinger K (2009) Increase in NADPH diaphorase positive neurons in the rat spinal trigeminal nucleus following infusion of a nitric oxide donor—evidence for a feed-forward process in nitric oxide production involved in trigeminal nociception. Cephalalgia. doi:10.1111/j.1468-2982.2008.01791.x [Epub ahead of print]

  • Schoenen J (2006) Neurophysiological features of the migrainous brain. Neurol Sci 27(Suppl 2):S77–S81

    Article  PubMed  Google Scholar 

  • Schwenger N, Dux M, De Col R, Carr R, Messlinger K (2007) 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 27:481–491

    Article  PubMed  CAS  Google Scholar 

  • Shimomura T, Murakami F, Kotani K, Ikawa S, Kono S (1999) Platelet nitric oxide metabolites in migraine. Cephalalgia 19:218–222

    Article  PubMed  CAS  Google Scholar 

  • Silberstein SD (1992) Advances in understanding the pathophysiology of headache. Neurology 42:6–10

    PubMed  CAS  Google Scholar 

  • Steiger HJ, Meakin CJ (1984) The meningeal representation in the trigeminal ganglion—an experimental study in the cat. Headache 24:305–309

    Article  PubMed  CAS  Google Scholar 

  • Storer RJ, Goadsby PJ (1997) Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 120:2171–2177

    Article  PubMed  Google Scholar 

  • Storer RJ, Akerman S, Goadsby PJ (2004) Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 142:1171–1181

    Article  PubMed  CAS  Google Scholar 

  • Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, Steiner T, Zwart JA (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27:193–210

    Article  PubMed  Google Scholar 

  • Strassman AM, Raymond SA (1997) On the origin of headaches. Endeavour 21:97–100

    Article  PubMed  CAS  Google Scholar 

  • Strassman A, Mason P, Moskowitz M, Maciewicz R (1986) Response of brainstem trigeminal neurons to electrical stimulation of the dura. Brain Res 379:242–250

    Article  PubMed  CAS  Google Scholar 

  • Strassman AM, Mineta Y, Vos BP (1994a) Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat. J Neurosci 14:3725–3735

    PubMed  CAS  Google Scholar 

  • Strassman AM, Potrebic S, Maciewicz RJ (1994b) Anatomical properties of brainstem trigeminal neurons that respond to electrical stimulation of dural blood vessels. J Comp Neurol 346:349–365

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Strecker T, Dux M, Messlinger K (2002) Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. J Vasc Res 39:489–496

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, Fukuuchi Y, Koto A, Naganuma Y, Isozumi K, Konno S, Gotoh J, Shimizu T (1994) Distribution and origins of cerebrovascular NADPH-diaphorase-containing nerve fibers in the rat. J Auton Nerv Syst 49 Suppl:S51–S54

    Google Scholar 

  • Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L (1999) Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst 76:176–183

    Article  PubMed  CAS  Google Scholar 

  • Tani E, Shiosaka S, Sato M, Ishikawa T, Tohyama M (1990) Histamine acts directly on calcitonin gene-related peptide- and substance P-containing trigeminal ganglion neurons as assessed by calcium influx and immunocytochemistry. Neurosci Lett 115:171–176

    Article  PubMed  CAS  Google Scholar 

  • Tassorelli C, Joseph SA (1995a) NADPH-diaphorase activity and Fos expression in brain nuclei following nitroglycerin administration. Brain Res 695:37–44

    Article  PubMed  CAS  Google Scholar 

  • Tassorelli C, Joseph SA (1995b) Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 682:167–181

    Article  PubMed  CAS  Google Scholar 

  • Thomsen LL, Olesen J (2001) Nitric oxide in primary headaches. Curr Opin Neurol 14:315–321

    Article  PubMed  CAS  Google Scholar 

  • Tracey I, Mantyh PW (2007) The cerebral signature for pain perception and its modulation. Neuron 55:377–391

    Article  PubMed  CAS  Google Scholar 

  • Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J (2005) No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 58:561–568

    Article  PubMed  CAS  Google Scholar 

  • van den Maagdenberg AM, Haan J, Terwindt GM, Ferrari MD (2007) Migraine: gene mutations and functional consequences. Curr Opin Neurol 20:299–305

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Wall PD (1980) The role of substantia gelatinosa as a gate control. Res Publ Assoc Res Nerv Ment Dis 58:205–231

    PubMed  CAS  Google Scholar 

  • Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, Coenen HH, Diener HC (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660

    Article  PubMed  CAS  Google Scholar 

  • Welch KM (1997) Pathogenesis of migraine. Semin Neurol 17:335–341

    Article  PubMed  CAS  Google Scholar 

  • Welch KM (2005) Brain hyperexcitability: the basis for antiepileptic drugs in migraine prevention. Headache 45(Suppl 1):S25–S32

    Article  PubMed  Google Scholar 

  • Wessman M, Terwindt GM, Kaunisto MA, Palotie A, Ophoff RA (2007) Migraine: a complex genetic disorder. Lancet Neurol 6:521–532

    Article  PubMed  CAS  Google Scholar 

  • Wienecke T, Olesen J, Oturai PS, Ashina M (2008) Prostacyclin (epoprostenol) induces headache in healthy subjects. Pain

  • Williamson DJ, Hargreaves RJ (2001) Neurogenic inflammation in the context of migraine. Microsc Res Tech 53:167–178

    Article  PubMed  CAS  Google Scholar 

  • Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL (1997) Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia 17:518–524

    Article  PubMed  CAS  Google Scholar 

  • Yamamura H, Malick A, Chamberlin NL, Burstein R (1999) Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine. J Neurophysiol 81:479–493

    PubMed  CAS  Google Scholar 

  • Yao D, Sessle BJ (2008) Nitroglycerin facilitates calcitonin gene-related peptide-induced behavior. Neuroreport 19:1307–1311

    Article  PubMed  CAS  Google Scholar 

  • Zagami AS, Goadsby PJ, Edvinsson L (1990) Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides 16:69–75

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Winborn CS, Marquez DP, Russo AF (2007b) Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 27:2693–2703

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Karl Messlinger.

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This contribution is dedicated to the author’s academic teacher, Robert F. Schmidt.

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Messlinger, K. Migraine: where and how does the pain originate?. Exp Brain Res 196, 179–193 (2009). https://doi.org/10.1007/s00221-009-1756-y

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