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Kynurenines and headache

  • Basic Neurosciences, Genetics and Immunology - Review article
  • Published:
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Abstract

In parallel to serotonin synthesis, the major route of tryptophan catabolism is the kynurenine pathway, which produces neuroactive metabolites. Among these substances, kynurenic acid has potential neuroprotective action blocking glutamate release and glutamatergic neurotransmission. Glutamate is a key player in migraine pathogenesis; it is crucial in the communication of first and second-order neurons, and it has an important role in the genesis of cortical spreading depression, which is the electrophysiological correlate for migraine aura and may be involved in the activation of the trigeminal system. Thus, kynurenines may affect the pathogenesis directly, by acting on glutamate receptors and exerting other neuromodulatory effects, and indirectly via an altered serotonin metabolism. This work summarizes our current results regarding the role of the kynurenine system in trigeminal activation and other events occurring during migraine headache.

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References

  • Ayata C, Moskowitz MA (2006) Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion. Am J Physiol Heart Circ Physiol 290:H1837–H1841

    Article  PubMed  CAS  Google Scholar 

  • Barbiroli B, Montagna P, Cortelli P, Martinelli P, Sacquegna T, Zaniol P, Lugaresi E (1990) Complicated migraine studied by phosphorus magnetic resonance spectroscopy. Cephalalgia 10:263–272

    Article  PubMed  CAS  Google Scholar 

  • Barbiroli B, Montagna P, Cortelli P, Funicello R, Iotti S, Monari L, Pierangeli G, Zaniol P, Lugaresi E (1992) Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology 42:1209–1214

    PubMed  CAS  Google Scholar 

  • Basarsky TA, Feighan D, MacVicar BA (1999) Glutamate release through volume-activated channels during spreading depression. J Neurosci 19:6439–6445

    PubMed  CAS  Google Scholar 

  • Beadle GW, Mitchell HK, Nyc JF (1947) Kynurenine as an intermediate in the formation of nicotinic acid from tryptophane by neurospora. Proc Natl Acad Sci USA 33:155–158

    Article  PubMed  CAS  Google Scholar 

  • Begon S, Pickering G, Eschalier A, Mazur A, Rayssiguier Y, Dubray C (2001) Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats. Br J Pharmacol 134:1227–1236

    Article  PubMed  CAS  Google Scholar 

  • Behan WM, McDonald M, Darlington LG, Stone TW (1999) Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol 128:1754–1760

    Article  PubMed  CAS  Google Scholar 

  • Bertolino M, Vicini S, Costa E (1989) Kynurenic acid inhibits the activation of kainic and N-methyl-d-aspartic acid-sensitive ionotropic receptors by a different mechanism. Neuropharmacology 28:453–457

    Article  PubMed  CAS  Google Scholar 

  • Birch PJ, Grossman CJ, Hayes AG (1988) Kynurenate and FG9041 have both competitive and non-competitive antagonist actions at excitatory amino acid receptors. Eur J Pharmacol 151:313–315

    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 

  • Borroni B, Brambilla C, Liberini P, Rao R, Archetti S, Gipponi S, Volta GD, Padovani A (2005) Functional serotonin 5-HTTLPR polymorphism is a risk factor for migraine with aura. J Headache Pain 6:182–184

    Article  PubMed  CAS  Google Scholar 

  • Burnet PW, Harrison PJ, Goodwin GM, Battersby S, Ogilvie AD, Olesen J, Russell MB (1997) Allelic variation in the serotonin 5-HT2C receptor gene and migraine. Neuroreport 8:2651–2653

    Article  PubMed  CAS  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, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH (2000) An association between migraine and cutaneous allodynia. Ann Neurol 47:614–624

    Article  PubMed  CAS  Google Scholar 

  • Cananzi AR, D’Andrea G, Perini F, Zamberlan F, Welch KM (1995) Platelet and plasma levels of glutamate and glutamine in migraine with and without aura. Cephalalgia 15:132–135

    Article  PubMed  CAS  Google Scholar 

  • Carlton SM, Hargett GL, Coggeshall RE (1995) Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 197:25–28

    Article  PubMed  CAS  Google Scholar 

  • Chabriat H, Danchot J, Michel P, Joire JE, Henry P (1999) Precipitating factors of headache. A prospective study in a national control-matched survey in migraineurs and nonmigraineurs. Headache 39:335–338

    Article  PubMed  CAS  Google Scholar 

  • Chapman V, Dickenson AH (1995) Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones. Brain Res 703:45–50

    Article  PubMed  CAS  Google Scholar 

  • Chiang CY, Hu JW, Sessle BJ (1997) NMDA receptor involvement in neuroplastic changes induced by neonatal capsaicin treatment in trigeminal nociceptive neurons. J Neurophysiol 78:2799–2803

    PubMed  CAS  Google Scholar 

  • Christoph T, Reissmuller E, Schiene K, Englberger W, Chizh BA (2005) Antiallodynic effects of NMDA glycine(B) antagonists in neuropathic pain: possible peripheral mechanisms. Brain Res 1048:218–227

    Article  PubMed  CAS  Google Scholar 

  • Chuquet J, Hollender L, Nimchinsky EA (2007) High-resolution in vivo imaging of the neurovascular unit during spreading depression. J Neurosci 27:4036–4044

    Article  PubMed  CAS  Google Scholar 

  • de Carvalho LP, Bochet P, Rossier J (1996) The endogenous agonist quinolinic acid and the nonendogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem Int 28:445–452

    Article  PubMed  Google Scholar 

  • Dickenson AH, Chapman V, Green GM (1997) The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol 28:633–638

    Article  PubMed  CAS  Google Scholar 

  • Diener HC (1997) Positron emission tomography studies in headache. Headache 37:622–625

    Article  PubMed  CAS  Google Scholar 

  • Dykens JA, Sullivan SG, Stern A (1987) Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol 36:211–217

    Article  PubMed  CAS  Google Scholar 

  • Eastman CL, Guilarte TR (1990) The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 15:1101–1107

    Article  PubMed  CAS  Google Scholar 

  • Ebersberger A, Averbeck B, Messlinger K, Reeh PW (1999) 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 

  • Ennis M, Aston-Jones G, Shiekhattar R (1992) Activation of locus coeruleus neurons by nucleus paragigantocellularis or noxious sensory stimulation is mediated by intracoerulear excitatory amino acid neurotransmission. Brain Res 598:185–195

    Article  PubMed  CAS  Google Scholar 

  • Erdal ME, Herken H, Yilmaz M, Bayazit YA (2001) Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine. J Neurol Sci 188:99–101

    Article  PubMed  CAS  Google Scholar 

  • Erdal N, Herken H, Yilmaz M, Erdal E, Bayazit YA (2007) The A218C polymorphism of tryptophan hydroxylase gene and migraine. J Clin Neurosci 14:249–251

    Article  PubMed  CAS  Google Scholar 

  • Fabricius M, Jensen LH, Lauritzen M (1993) Microdialysis of interstitial amino acids during spreading depression and anoxic depolarization in rat neocortex. Brain Res 612:61–69

    Article  PubMed  CAS  Google Scholar 

  • Faria LC, Mody I (2004) Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex. J Neurophysiol 92:2610–2614

    Article  PubMed  CAS  Google Scholar 

  • Ferrari MD, Saxena PR (1993) On serotonin and migraine: a clinical and pharmacological review. Cephalalgia 13:151–165

    Article  PubMed  CAS  Google Scholar 

  • Ferrari MD, Odink J, Tapparelli C, Van Kempen GM, Pennings EJ, Bruyn GW (1989) Serotonin metabolism in migraine. Neurology 39:1239–1242

    PubMed  CAS  Google Scholar 

  • Ferrari MD, Odink J, Bos KD, Malessy MJ, Bruyn GW (1990) Neuroexcitatory plasma amino acids are elevated in migraine. Neurology 40:1582–1586

    PubMed  CAS  Google Scholar 

  • Filic V, Vladic A, Stefulj J, Cicin-Sain L, Balija M, Sucic Z, Jernej B (2005) Monoamine oxidases A and B gene polymorphisms in migraine patients. J Neurol Sci 228:149–153

    Article  PubMed  CAS  Google Scholar 

  • Filla SA, Winter MA, Johnson KW, Bleakman D, Bell MG, Bleisch TJ, Castano AM, Clemens-Smith A, del PM, Dieckman DK, Dominguez E, Escribano A, Ho KH, Hudziak KJ, Katofiasc MA, Martinez-Perez JA, Mateo A, Mathes BM, Mattiuz EL, Ogden AM, Phebus LA, Stack DR, Stratford RE, Ornstein PL (2002) Ethyl (3S,4aR,6S,8aR)-6-(4-ethoxycarbonylimidazol-1-ylmethyl)decahydroiso-quinoline-3-carboxylic ester: a prodrug of a GluR5 kainate receptor antagonist active in two animal models of acute migraine. J Med Chem 45:4383–4386

    Article  PubMed  CAS  Google Scholar 

  • Gigler G, Szenasi G, Simo A, Levay G, Harsing LG Jr, Sas K, Vecsei L, Toldi J (2007) Neuroprotective effect of l-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils. Eur J Pharmacol 564:116–122

    Article  PubMed  CAS  Google Scholar 

  • Goadsby PJ, Classey JD (2000) Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res 875:119–124

    Article  PubMed  CAS  Google Scholar 

  • Gobaille S, Kemmel V, Brumaru D, Dugave C, Aunis D, Maitre M (2008) Xanthurenic acid distribution, transport, accumulation and release in the rat brain. J Neurochem 105:982–993

    Article  PubMed  CAS  Google Scholar 

  • Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA (1996) Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716

    Article  PubMed  CAS  Google Scholar 

  • Guidetti P, Schwarcz R (1999) 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur J Neurosci 11:3857–3863

    Article  PubMed  CAS  Google Scholar 

  • Guidetti P, Okuno E, Schwarcz R (1997) Characterization of rat brain kynurenine aminotransferases I and II. J Neurosci Res 50:457–465

    Article  PubMed  CAS  Google Scholar 

  • Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R (2007) Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem 102:103–111

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, Brew BJ (2001) IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment. J Interferon Cytokine Res 21:1097–1101

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ (2003) Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 527:105–112

    Article  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Cullen KM, Lim CK, Smythe GA, Garner B, Kapoor V, Takikawa O, Brew BJ (2007) Characterization of the kynurenine pathway in human neurons. J Neurosci 27:12884–12892

    Article  PubMed  CAS  Google Scholar 

  • Haghir H, Kovac S, Speckmann EJ, Zilles K, Gorji A (2009) Patterns of neurotransmitter receptor distributions following cortical spreading depression. Neuroscience 163:1340–1352

    Article  PubMed  CAS  Google Scholar 

  • Hajos M, Engberg G (1990) Kynurenic acid blocks chemogenic nociception. J Pharm Pharmacol 42:373–374

    Article  PubMed  CAS  Google Scholar 

  • Hamel E (2007) Serotonin and migraine: biology and clinical implications. Cephalalgia 27:1293–1300

    Article  PubMed  CAS  Google Scholar 

  • Henning EC, Meng X, Fisher M, Sotak CH (2005) Visualization of cortical spreading depression using manganese-enhanced magnetic resonance imaging. Magn Reson Med 53:851–857

    Article  PubMed  Google Scholar 

  • Heyliger SO, Goodman CB, Ngong JM, Soliman KF (1998) The analgesic effects of tryptophan and its metabolites in the rat. Pharmacol Res 38:243–250

    Article  PubMed  CAS  Google Scholar 

  • Hill RG, Salt TE (1982) An ionophoretic study of the responses of rat caudal trigeminal nucleus neurones to non-noxious mechanical sensory stimuli. J Physiol 327:65–78

    PubMed  CAS  Google Scholar 

  • Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473

    PubMed  CAS  Google Scholar 

  • Humphrey PP (1991) 5-Hydroxytryptamine and the pathophysiology of migraine. J Neurol 238(Suppl 1):S38–S44

    Article  PubMed  Google Scholar 

  • Jarvis CR, Anderson TR, Andrew RD (2001) Anoxic depolarization mediates acute damage independent of glutamate in neocortical brain slices. Cereb Cortex 11:249–259

    Article  PubMed  CAS  Google Scholar 

  • Jhamandas K, Boegman RJ, Beninger RJ, Bialik M (1990) Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites. Brain Res 529:185–191

    Article  PubMed  CAS  Google Scholar 

  • Jiang M, Behbehani MM (2001) Physiological characteristics of the projection pathway from the medial preoptic to the nucleus raphe magnus of the rat and its modulation by the periaqueductal gray. Pain 94:139–147

    Article  PubMed  CAS  Google Scholar 

  • Johnson MP, Griffiths LR (2005) A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach. J Hum Genet 50:607–610

    Article  PubMed  CAS  Google Scholar 

  • Johnson MP, Lea RA, Curtain RP, Macmillan JC, Griffiths LR (2003) An investigation of the 5-HT2C receptor gene as a migraine candidate gene. Am J Med Genet B Neuropsychiatr Genet 117B:86–89

    Article  PubMed  Google Scholar 

  • Juhasz G, Zsombok T, Laszik A, Gonda X, Sotonyi P, Faludi G, Bagdy G (2003) Association analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine. J Neurogenet 17:231–240

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo DC (2004) Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 62:1297–1302

    PubMed  CAS  Google Scholar 

  • Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated with N-methyl-d-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52:1319–1328

    Article  PubMed  CAS  Google Scholar 

  • Kiss C, Shepard PD, Bari F, Schwarcz R (2004) Cortical spreading depression augments kynurenate levels and reduces malonate toxicity in the rat cortex. Brain Res 1002:129–135

    Article  PubMed  CAS  Google Scholar 

  • Knyihar-Csillik E, Chadaide Z, Okuno E, Krisztin-Peva B, Toldi J, Varga C, Molnar A, Csillik B, Vecsei L (2004) Kynurenine aminotransferase in the supratentorial dura mater of the rat: effect of stimulation of the trigeminal ganglion. Exp Neurol 186:242–247

    Article  PubMed  CAS  Google Scholar 

  • Knyihar-Csillik E, Toldi J, Mihaly A, Krisztin-Peva B, Chadaide Z, Nemeth H, Fenyo R, Vecsei L (2007) Kynurenine in combination with probenecid mitigates the stimulation-induced increase of c-fos immunoreactivity of the rat caudal trigeminal nucleus in an experimental migraine model. J Neural Transm 114:417–421

    Article  PubMed  CAS  Google Scholar 

  • Knyihar-Csillik E, Mihaly A, Krisztin-Peva B, Robotka H, Szatmari I, Fulop F, Toldi J, Csillik B, Vecsei L (2008) The kynurenate analog SZR-72 prevents the nitroglycerol-induced increase of c-fos immunoreactivity in the rat caudal trigeminal nucleus: comparative studies of the effects of SZR-72 and kynurenic acid. Neurosci Res 61:429–432

    Article  PubMed  CAS  Google Scholar 

  • Kolhekar R, Murphy S, Gebhart GF (1997) Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat. Pain 71:31–40

    Article  PubMed  CAS  Google Scholar 

  • Kotani K, Shimomura T, Shimomura F, Ikawa S, Nanba E (2002) A polymorphism in the serotonin transporter gene regulatory region and frequency of migraine attacks. Headache 42:893–895

    Article  PubMed  Google Scholar 

  • Kristensen JD, Post C, Gordh T Jr, Svensson BA (1993) Spinal cord morphology and antinociception after chronic intrathecal administration of excitatory amino acid antagonists in the rat. Pain 54:309–316

    Article  PubMed  CAS  Google Scholar 

  • Lance JW, Lambert GA, Goadsby PJ, Duckworth JW (1983) Brainstem influences on the cephalic circulation: experimental data from cat and monkey of relevance to the mechanism of migraine. Headache 23:258–265

    Article  PubMed  CAS  Google Scholar 

  • Lapin IP (1978) Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transm 42:37–43

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lauritzen M, Jorgensen MB, Diemer NH, Gjedde A, Hansen AJ (1982) Persistent oligemia of rat cerebral cortex in the wake of spreading depression. Ann Neurol 12:469–474

    Article  PubMed  CAS  Google Scholar 

  • Lauritzen M, Rice ME, Okada Y, Nicholson C (1988) Quisqualate, kainate and NMDA can initiate spreading depression in the turtle cerebellum. Brain Res 475:317–327

    Article  PubMed  CAS  Google Scholar 

  • Leao AAP (1944) Spreading depression of activity in cerebral cortex. J Neurophysiol 7:359–390

    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 H, Wang H, Sheng M, Jan LY, Jan YN, Basbaum AI (1994) Evidence for presynaptic N-methyl-d-aspartate autoreceptors in the spinal cord dorsal horn. Proc Natl Acad Sci USA 91:8383–8387

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Chang GQ, Jiao YQ, Simon SA (1998) Neuronal nicotinic acetylcholine receptors in rat trigeminal ganglia. Brain Res 809:238–245

    Article  PubMed  CAS  Google Scholar 

  • Maassen VA, Vergouwe MN, Ophoff RA, Naylor SL, Dauwerse HG, Saxena PR, Ferrari MD, Frants RR (1998a) Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients. Am J Med Genet 77:415–420

    Article  Google Scholar 

  • Maassen VA, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR (1998b) 5-HT1B receptor polymorphism and clinical response to sumatriptan. Headache 38:288–291

    Article  Google Scholar 

  • MacKenzie CR, Gonzalez RG, Kniep E, Roch S, Daubener W (1999) Cytokine mediated regulation of interferon-gamma-induced IDO activation. Adv Exp Med Biol 467:533–539

    Article  PubMed  CAS  Google Scholar 

  • Martelletti P, Stirparo G, Rinaldi C, Frati L, Giacovazzo M (1993) Disruption of the immunopeptidergic network in dietary migraine. Headache 33:524–527

    Article  PubMed  CAS  Google Scholar 

  • Martelletti P, Stirparo G, Morrone S, Rinaldi C, Giacovazzo M (1997) Inhibition of intercellular adhesion molecule-1 (ICAM-1), soluble ICAM-1 and interleukin-4 by nitric oxide expression in migraine patients. J Mol Med 75:448–453

    Article  PubMed  CAS  Google Scholar 

  • Martinez F, Castillo J, Rodriguez JR, Leira R, Noya M (1993) Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks. Cephalalgia 13:89–93

    Article  PubMed  CAS  Google Scholar 

  • Marziniak M, Mossner R, Benninghoff J, Syagailo YV, Lesch KP, Sommer C (2004) Association analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine. J Neural Transm 111:603–609

    Article  PubMed  CAS  Google Scholar 

  • Marziniak M, Mossner R, Schmitt A, Lesch KP, Sommer C (2005) A functional serotonin transporter gene polymorphism is associated with migraine with aura. Neurology 64:157–159

    Article  PubMed  CAS  Google Scholar 

  • Mavromichalis I, Zaramboukas T, Giala MM (1995) Migraine of gastrointestinal origin. Eur J Pediatr 154:406–410

    Article  PubMed  CAS  Google Scholar 

  • McGehee DS, Heath MJ, Gelber S, Devay P, Role LW (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269:1692–1696

    Article  PubMed  CAS  Google Scholar 

  • Mecs L, Tuboly G, Nagy E, Benedek G, Horvath G (2009) The peripheral antinociceptive effects of endomorphin-1 and kynurenic acid in the rat inflamed joint model. Anesth Analg 109:1297–1304

    Article  PubMed  CAS  Google Scholar 

  • Mitsikostas DD, Sanchez del RM, Waeber C, Moskowitz MA, Cutrer FM (1998) The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 76:239–248

    Article  PubMed  CAS  Google Scholar 

  • Mitsikostas DD, Sanchez del RM, Waeber C, Huang Z, Cutrer FM, Moskowitz MA (1999) Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br J Pharmacol 127:623–630

    Article  PubMed  CAS  Google Scholar 

  • Montagna P, Cortelli P, Barbiroli B (1994) Magnetic resonance spectroscopy studies in migraine. Cephalalgia 14:184–193

    Article  PubMed  CAS  Google Scholar 

  • Mortimer MJ, Kay J, Gawkrodger DJ, Jaron A, Barker DC (1993) The prevalence of headache and migraine in atopic children: an epidemiological study in general practice. Headache 33:427–431

    Article  PubMed  CAS  Google Scholar 

  • Moskowitz MA, Nozaki K, Kraig RP (1993) Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 13:1167–1177

    PubMed  CAS  Google Scholar 

  • Munno I, Centonze V, Marinaro M, Bassi A, Lacedra G, Causarano V, Nardelli P, Cassiano MA, Albano O (1998) Cytokines and migraine: increase of IL-5 and IL-4 plasma levels. Headache 38:465–467

    Article  PubMed  CAS  Google Scholar 

  • Munno I, Marinaro M, Bassi A, Cassiano MA, Causarano V, Centonze V (2001) Immunological aspects in migraine: increase of IL-10 plasma levels during attack. Headache 41:764–767

    Article  PubMed  CAS  Google Scholar 

  • Murphy AZ, Behbehani MM (1993) Electrophysiological characterization of the projection from the nucleus raphe magnus to the lateral reticular nucleus: possible role of an excitatory amino acid in synaptic activation. Brain Res 606:68–78

    Article  PubMed  CAS  Google Scholar 

  • Nasstrom J, Karlsson U, Post C (1992) Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 212:21–29

    Article  PubMed  CAS  Google Scholar 

  • Nellgard B, Wieloch T (1992) NMDA-receptor blockers but not NBQX, an AMPA-receptor antagonist, inhibit spreading depression in the rat brain. Acta Physiol Scand 146:497–503

    Article  PubMed  CAS  Google Scholar 

  • Nyholt DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR (1996) Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor gene. Cephalalgia 16:463–467

    Article  PubMed  CAS  Google Scholar 

  • Obeidat AS, Jarvis CR, Andrew RD (2000) Glutamate does not mediate acute neuronal damage after spreading depression induced by O2/glucose deprivation in the hippocampal slice. J Cereb Blood Flow Metab 20:412–422

    Article  PubMed  CAS  Google Scholar 

  • Obrenovitch TP (2001) Quinolinic acid accumulation during neuroinflammation. Does it imply excitotoxicity? Ann N Y Acad Sci 939:1–10

    Article  PubMed  CAS  Google Scholar 

  • Obrenovitch TP, Urenjak J (2003) Accumulation of quinolinic acid with neuroinflammation: does it mean excitotoxicity? Adv Exp Med Biol 527:147–154

    Article  PubMed  CAS  Google Scholar 

  • Ohshiro H, Tonai-Kachi H, Ichikawa K (2008) GPR35 is a functional receptor in rat dorsal root ganglion neurons. Biochem Biophys Res Commun 365:344–348

    Article  PubMed  CAS  Google Scholar 

  • Oshinsky ML, Luo J (2006) Neurochemistry of trigeminal activation in an animal model of migraine. Headache 46(Suppl 1):S39–S44

    Article  PubMed  Google Scholar 

  • Pardutz A, Krizbai I, Multon S, Vecsei L, Schoenen J (2000) Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport 11:3071–3075

    Article  PubMed  CAS  Google Scholar 

  • Pardutz A, Hoyk Z, Varga H, Vecsei L, Schoenen J (2007) Oestrogen-modulated increase of calmodulin-dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin. Cephalalgia 27:46–53

    Article  PubMed  CAS  Google Scholar 

  • Park JW, Han SR, Yang DW, Kim YI, Lee KS (2006) Serotonin transporter protein polymorphism and harm avoidance personality in migraine without aura. Headache 46:991–996

    Article  PubMed  Google Scholar 

  • Peikert A, Wilimzig C, Kohne-Volland R (1996) Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 16:257–263

    Article  PubMed  CAS  Google Scholar 

  • Peters O, Schipke CG, Hashimoto Y, Kettenmann H (2003) Different mechanisms promote astrocyte Ca2+ waves and spreading depression in the mouse neocortex. J Neurosci 23:9888–9896

    PubMed  CAS  Google Scholar 

  • Pietrobon D (2007) Familial hemiplegic migraine. Neurotherapeutics 4:274–284

    Article  PubMed  CAS  Google Scholar 

  • Ping HX, Wu HQ, Liu GQ (1990) Modulation of neuronal activity of locus coeruleus in rats induced by excitatory amino acids. Zhongguo Yao Li Xue Bao 11:193–195

    PubMed  CAS  Google Scholar 

  • Pinnock RD (1992) Activation of kappa-opioid receptors depresses electrically evoked excitatory postsynaptic potentials on 5-HT-sensitive neurones in the rat dorsal raphe nucleus in vitro. Brain Res 583:237–246

    Article  PubMed  CAS  Google Scholar 

  • Politi V, Lavaggi MV, Di Stazio G, Margonelli A (1991) Indole-3-pyruvic acid as a direct precursor of kynurenic acid. Adv Exp Med Biol 294:515–518

    PubMed  CAS  Google Scholar 

  • Politi V, D’Alessio S, Di Stazio G, De Luca G (1996) Antioxidant properties of indole-3-pyruvic acid. Adv Exp Med Biol 398:291–298

    Article  PubMed  CAS  Google Scholar 

  • Prescott C, Weeks AM, Staley KJ, Partin KM (2006) Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett 402:108–112

    Article  PubMed  CAS  Google Scholar 

  • Quartu M, Serra MP, Ambu R, Lai ML, Del FM (2002) AMPA-type glutamate receptor subunits 2/3 in the human trigeminal sensory ganglion and subnucleus caudalis from prenatal ages to adulthood. Mech Ageing Dev 123:463–471

    Article  PubMed  CAS  Google Scholar 

  • Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM (1989) Low brain magnesium in migraine. Headache 29:416–419

    Article  PubMed  CAS  Google Scholar 

  • Ren K, Williams GM, Hylden JL, Ruda MA, Dubner R (1992) The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats. Eur J Pharmacol 219:235–243

    Article  PubMed  CAS  Google Scholar 

  • Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143

    Article  PubMed  CAS  Google Scholar 

  • Russell MB, Olesen J (1996) A nosographic analysis of the migraine aura in a general population. Brain 119(Pt 2):355–361

    Article  PubMed  Google Scholar 

  • Sahara Y, Noro N, Iida Y, Soma K, Nakamura Y (1997) Glutamate receptor subunits GluR5 and KA-2 are coexpressed in rat trigeminal ganglion neurons. J Neurosci 17:6611–6620

    PubMed  CAS  Google Scholar 

  • Sandor PS, Di Clemente L, Coppola G, Saenger U, Fumal A, Magis D, Seidel L, Agosti RM, Schoenen J (2005a) Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology 64:713–715

    Article  PubMed  CAS  Google Scholar 

  • Sandor PS, Dydak U, Schoenen J, Kollias SS, Hess K, Boesiger P, Agosti RM (2005b) MR-spectroscopic imaging during visual stimulation in subgroups of migraine with aura. Cephalalgia 25:507–518

    Article  PubMed  CAS  Google Scholar 

  • Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F (2004) LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 24:596–602

    Article  PubMed  CAS  Google Scholar 

  • Sangiorgi S, Mochi M, Riva R, Cortelli P, Monari L, Pierangeli G, Montagna P (1994) Abnormal platelet mitochondrial function in patients affected by migraine with and without aura. Cephalalgia 14:21–23

    Article  PubMed  CAS  Google Scholar 

  • Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, Floridi A, Calabresi P (2006) Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 46:200–207

    Article  PubMed  Google Scholar 

  • Sato K, Kiyama H, Park HT, Tohyama M (1993) AMPA, KA and NMDA receptors are expressed in the rat DRG neurones. Neuroreport 4:1263–1265

    Article  PubMed  CAS  Google Scholar 

  • Schoenen J, Jacquy J, Lenaerts M (1998) Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 50:466–470

    PubMed  CAS  Google Scholar 

  • Schuh-Hofer S, Richter M, Geworski L, Villringer A, Israel H, Wenzel R, Munz DL, Arnold G (2007) Increased serotonin transporter availability in the brainstem of migraineurs. J Neurol 254:789–796

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303:1–10

    Article  PubMed  CAS  Google Scholar 

  • Shigemoto R, Ohishi H, Nakanishi S, Mizuno N (1992) Expression of the mRNA for the rat NMDA receptor (NMDAR1) in the sensory and autonomic ganglion neurons. Neurosci Lett 144:229–232

    Article  PubMed  CAS  Google Scholar 

  • Shimomura T, Araga S, Esumi E, Takahashi K (1991) Decreased serum interleukin-2 level in patients with chronic headache. Headache 31:310–313

    Article  PubMed  CAS  Google Scholar 

  • Sicuteri F, Testi A, Anselmi B (1961) Biochemical investigations in headache: increase in hydroxytryindoleacetic acid excretion during migraine attacks. Int Arch Allergy 19:55–58

    Google Scholar 

  • Smith DH, Okiyama K, Thomas MJ, McIntosh TK (1993) Effects of the excitatory amino acid receptor antagonists kynurenate and indole-2-carboxylic acid on behavioral and neurochemical outcome following experimental brain injury. J Neurosci 13:5383–5392

    PubMed  CAS  Google Scholar 

  • Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81:1065–1096

    PubMed  CAS  Google Scholar 

  • Song XJ, Zhao ZQ (1993) Differential effects of NMDA and non-NMDA receptor antagonists on spinal cutaneous vs muscular nociception in the cat. Neuroreport 4:17–20

    Article  PubMed  CAS  Google Scholar 

  • Storer RJ, Goadsby PJ (1999) Trigeminovascular nociceptive transmission involves N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. Neuroscience 90:1371–1376

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

    Article  PubMed  CAS  Google Scholar 

  • Tallaksen-Greene SJ, Young AB, Penney JB, Beitz AJ (1992) Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci Lett 141:79–83

    Article  PubMed  CAS  Google Scholar 

  • Taniguchi Y, Tonai-Kachi H, Shinjo K (2006) Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35. FEBS Lett 580:5003–5008

    Article  PubMed  CAS  Google Scholar 

  • Tan-No K, Esashi A, Nakagawasai O, Niijima F, Furuta S, Sato T, Satoh S, Yasuhara H, Tadano T (2007) Intrathecally administered d-cycloserine produces nociceptive behavior through the activation of N-methyl-d-aspartate receptor ion-channel complex acting on the glycine recognition site. J Pharmacol Sci 104:39–45

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T, Souza DO (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627

    Article  PubMed  CAS  Google Scholar 

  • Terwindt GM, Ferrari MD, Tijhuis M, Groenen SM, Picavet HS, Launer LJ (2000) The impact of migraine on quality of life in the general population: the GEM study. Neurology 55:624–629

    PubMed  CAS  Google Scholar 

  • Todt U, Freudenberg J, Goebel I, Heinze A, Heinze-Kuhn K, Rietschel M, Gobel H, Kubisch C (2006) Variation of the serotonin transporter gene SLC6A4 in the susceptibility to migraine with aura. Neurology 67:1707–1709

    Article  PubMed  CAS  Google Scholar 

  • Turski WA, Nakamura M, Todd WP, Carpenter BK, Whetsell WO Jr, Schwarcz R (1988) Identification and quantification of kynurenic acid in human brain tissue. Brain Res 454:164–169

    Article  PubMed  CAS  Google Scholar 

  • Tyce GM (1990) Origin and metabolism of serotonin. J Cardiovasc Pharmacol 16(Suppl 3):S1–S7

    PubMed  CAS  Google Scholar 

  • Valentino RJ, Bey V, Pernar L, Commons KG (2003) Substance P Acts through local circuits within the rat dorsal raphe nucleus to alter serotonergic neuronal activity. J Neurosci 23:7155–7159

    PubMed  CAS  Google Scholar 

  • Vamos E, Pardutz A, Varga H, Bohar Z, Tajti J, Fulop F, Toldi J, Vecsei L (2009) l-kynurenine combined with probenecid and the novel synthetic kynurenic acid derivative attenuate nitroglycerin-induced nNOS in the rat caudal trigeminal nucleus. Neuropharmacology 57:425–429

    Article  PubMed  CAS  Google Scholar 

  • Vamos E, Fejes A, Koch J, Tajti J, Fulop F, Toldi J, Pardutz A, Vecsei L (2010) Kynurenate derivative attenuates the nitroglycerin-induced CamKIIalpha and CGRP expression changes. Headache 50:834–843

    Google Scholar 

  • Velling DA, Dodick DW, Muir JJ (2003) Sustained-release niacin for prevention of migraine headache. Mayo Clin Proc 78:770–771

    Article  PubMed  Google Scholar 

  • Vikelis M, Mitsikostas DD (2007) The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 6:251–257

    Article  PubMed  CAS  Google Scholar 

  • Vilagi I, Klapka N, Luhmann HJ (2001) Optical recording of spreading depression in rat neocortical slices. Brain Res 898:288–296

    Article  PubMed  CAS  Google Scholar 

  • Wang XM, Mokha SS (1996) Opioids modulate N-methyl-d-aspartic acid (NMDA)-evoked responses of trigeminothalamic neurons. J Neurophysiol 76:2093–2096

    PubMed  CAS  Google Scholar 

  • Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem 281:22021–22028

    Article  PubMed  CAS  Google Scholar 

  • Watanabe M, Mishina M, Inoue Y (1994) Distinct gene expression of the N-methyl-d-aspartate receptor channel subunit in peripheral neurons of the mouse sensory ganglia and adrenal gland. Neurosci Lett 165:183–186

    Article  PubMed  CAS  Google Scholar 

  • Watanabe H, Kuwabara T, Ohkubo M, Tsuji S, Yuasa T (1996) Elevation of cerebral lactate detected by localized 1H-magnetic resonance spectroscopy in migraine during the interictal period. Neurology 47:1093–1095

    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, Ramadan NM (1995) Mitochondria, magnesium and migraine. J Neurol Sci 134:9–14

    Article  PubMed  CAS  Google Scholar 

  • Welch KM, Nagesh V, Aurora SK, Gelman N (2001) Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 41:629–637

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Wolf H (1974) The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. Scand J Clin Lab Invest 136:1–186

    CAS  Google Scholar 

  • Yamamoto T, Yaksh TL (1992) Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain 49:121–128

    Article  PubMed  CAS  Google Scholar 

  • Yang XS, Xu XP, Yang QD (2006) No association of C-1019G promoter polymorphism of 5-HT1A receptor gene with migraine. Eur J Neurol 13:533–535

    Article  PubMed  CAS  Google Scholar 

  • Yilmaz M, Erdal ME, Herken H, Cataloluk O, Barlas O, Bayazit YA (2001) Significance of serotonin transporter gene polymorphism in migraine. J Neurol Sci 186:27–30

    Article  PubMed  CAS  Google Scholar 

  • Yu P, Li Z, Zhang L, Tagle DA, Cai T (2006) Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family. Gene 365:111–118

    Article  PubMed  CAS  Google Scholar 

  • Zhang YQ, Ji GC, Wu GC, Zhao ZQ (2003) Kynurenic acid enhances electroacupuncture analgesia in normal and carrageenan-injected rats. Brain Res 966:300–307

    Article  PubMed  CAS  Google Scholar 

  • Zsizsik BK, Hardeland R (2002) Formation of kynurenic and xanthurenic acids from kynurenine and 3-hydroxykynurenine in the dinoflagellate Lingulodinium polyedrum: role of a novel, oxidative pathway. Comp Biochem Physiol C Toxicol Pharmacol 133:383–392

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants ETT 026-04, OTKA K75628 and TÁMOP-4.2.1/B-09/1/KONV-2010-0005—Creating the Center of Excellence at the University of Szeged. Oue thanks are due to David Durham for the linguistic correction of the manuscript.

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  1. Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged, 6725, Hungary

    Árpád Párdutz, Annamária Fejes, Zsuzsanna Bohár, Lilla Tar & László Vécsei

  2. Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

    József Toldi

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  1. Árpád Párdutz
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Correspondence to Árpád Párdutz.

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Párdutz, Á., Fejes, A., Bohár, Z. et al. Kynurenines and headache. J Neural Transm 119, 285–296 (2012). https://doi.org/10.1007/s00702-011-0665-y

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