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Elusive amines: migraine depends on biochemical abnormalities

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Abstract

The pathogenesis of migraine, as well as cluster headache (CH), is yet a debated question. In this review, we discuss the possible role of tyrosine and tryptophan metabolism in the pathogenesis of primary headaches, including the abnormalities in the synthesis of neurotransmitters. High level of dopamine, low level of norepinephrine, and very elevated levels of octopamine and synephrine were found in the plasma of episodic migraine without aura. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward increased decarboxylase and reduced hydroxylase enzyme activities, favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity. In addition, we present biochemical studies performed in chronic migraine (CM) and chronic tension-type headache patients (CTTH) to verify if the same anomalies are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine-related metabolites are present only in CM patients while tryptamine plasma levels were found significantly lower in both CM and CTTH patients. Because of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

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References

  1. Headache Classification Committee of the International Headache Society (IHS) (2018) The international classification of headache disorders, 3rd edition. Cephalagia 38(1):1–211

  2. Welch KMA (1987) Migraine a biobehavioral disorder. Arch Neurol 44:323–327

    Article  CAS  PubMed  Google Scholar 

  3. D’Andrea G, Leon A (2010) Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond. Neurol SciSuppl 1:S1–S7

    Google Scholar 

  4. D’Andrea G, Cananzi AR, Ferro Milone F, Joseph R, Grunfeld S, Welch KMA (1989) Platelet levels of glutamate and aspartate in normal subjects. Stroke 20(2):299–300

    Article  PubMed  Google Scholar 

  5. Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474

    Article  CAS  PubMed  Google Scholar 

  6. D’Andrea G, Nordera GP, Perini F, Allais G, Granella F (2007) Biochemistry of neuro-modulation in primary headaches: focus on tyrosine metabolism. Neurol Sci 28 (Suppl 2):S94–S96

  7. D’Andrea G, Terrazzino S, Fortin D, Cocco P, Balbi T (2003) Elusive amines and primary headaches: historical background and prospectives. Neurol Sci 24:S65–S67

    Article  PubMed  Google Scholar 

  8. Axelrod J, Saavedra JM (1977) Octopamine Nature 265:501–504

    Article  CAS  PubMed  Google Scholar 

  9. Cananzi AR, D’Andrea G, Perini F, Zamberaln F, Welch KMA (1995) Platelet plasma levels of glutamate and glutamine in migraine with and without aura. Cephalalgia 15(2):132–135

    Article  CAS  PubMed  Google Scholar 

  10. Welch KMA, D’Andrea G, Tepley N, Barkley G, Ramadan NM (1990) The concept of migraine as a state of central neuronal hyperexcitability. Neurol Clin 8:817–828

    Article  CAS  PubMed  Google Scholar 

  11. Cao Y, Welch KMA, Aurora S, Vikinsgtad EM (1999) Functional MRI-BOLD of visual triggered headache in patients with migraine.Arch Neurol 56:548–554

  12. Van Gelder N (1987) Calcium mobility and release associated with EEG abnormalities, migraine and epilepsy. Butterworths, Boston, pp 367–378

    Google Scholar 

  13. Prescot A, Becerra L, Pendse G, Shannon T et al (2009) Excitatory neurotransmitters in brain regions in interictal migraine patients. Mol Pain 5–34:1–11

    Google Scholar 

  14. Dela Aleja G, Ramos A, Mato-Abado A, Martinez-Salio A et al (2012) Higher glutamate to glutamine ratios in occipital regions in women with migraine during interictal state. Headache 53(2):365–375

    Article  Google Scholar 

  15. Aurora SK, Ahmad BK, Welch KM, Bhardhwaj P, Ramadan NM (1998) Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine. Neurology 50(4):1111–1114

    Article  CAS  PubMed  Google Scholar 

  16. Khedr EM, Ahmed MA, Mohamed KA (2006) Motor and visual cortical excitability in migraineurs patients with and without aura: transcranial magnetic stimulation. Neurophysiol Clin 36(1):13–18

    Article  PubMed  Google Scholar 

  17. Brighina F, Bolognini N, Cosentino G, Maccora S, Paladino P, Baschi R, Vallar G, Fierro B (2015) Visual cortex hyperexcitability in migraine in response to sound- induced flash illusions. Neurology 19;84(20):2057–61

  18. Maccora S, Bolognini N, Cosentino G, Baschi R, Vallar G, Fierro B, Brighina F (2020) Multisensorial perception in chronic migraine and the role of medication overuse. J Pain 21(7–8):919–929

    Article  CAS  PubMed  Google Scholar 

  19. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM (1989) Low brain magnesium and migraine. Headache 29(7):416–419

    Article  CAS  PubMed  Google Scholar 

  20. Van Harreveld A (1984) The nature of chick’s magnesium sensitive retinal spreading depression. J Neurobiol 15:333–334

    Article  PubMed  Google Scholar 

  21. Griffin NJ, Ruggiero L, Lipton RB, Silberstein SD et al (2003) Premonitory symptoms in migraine: an electronic diary study. Neurology 60(6):935–940

    Article  Google Scholar 

  22. Quintela E, Castillo J, Mnoz P, Pascual J (2006) Premonitory and resolution symptoms in migraine: a prospective study in 100 unselected patients. Cephalalgia 26(9):1051–1060

    Article  CAS  PubMed  Google Scholar 

  23. Demarquay G, Royet JP, Giroud P, Chazot G, Valade D, Ryvlin P (2006) Rating of olfactory judgement in migraine patients. Cephalalgia 26:1123–1130

    Article  CAS  PubMed  Google Scholar 

  24. Denuelle M, Fabre N, Payoux P, Chollet F, Geroud G (2007) Hypothalamic activation in spontaneous migraine attacks. Headache 47(10):1418–1426

    PubMed  Google Scholar 

  25. D’Andrea G, Terrazzino S, Leon A, Fortin D, Perini F, Granella F, Bussone G (2004) Elevated levels of circulating trace amines in primary headaches. Neurology 62:1701–1705

    Article  PubMed  Google Scholar 

  26. D’Andrea G, Granella F, Leone M, Perini F, Farruggio A, Bussone G (2006) Abnormal platelet trace amine profiles in migraine with and without aura. Cephalalgia 26(8):968–972

    Article  PubMed  Google Scholar 

  27. Moulton EA, Burstein R, Tully S, Hargreaves R, Becerra L, Borsook D (2008) Inter-ictal dysfunction descending modulatory centers in migraine patients. PLoS ONE 3(11):e3799

    Article  PubMed  PubMed Central  Google Scholar 

  28. Fumal A, Laureys S, Di Clemente L, Boly M, Bohotin V, Vandenheede M, Coppola GL, Salmon E, Kupers R, Shoenen J (2006) Orbitofrontal cortex involvement in chronic analgesic—overuse headache evolving from episodic migraine. Brain 129:543–550

    Article  PubMed  Google Scholar 

  29. Welch KMA, Cao Y, Aurora SK, Wiggins G, Vikingstad EM (1998) MRI of the occipital cortex, red nucleus and substantia nigra during visual aura of migraine. Neurology 51:1465–1469

    Article  CAS  PubMed  Google Scholar 

  30. Willer 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(7):658–660

    Article  Google Scholar 

  31. Altier N, Stewart J (1999) The tachinin NK-1 receptor antagonist RP-67580, infused into ventral tegmental area prevents stress induced analgesia in the formalin test. Physiol Behav 66:717–721

    Article  CAS  PubMed  Google Scholar 

  32. D’Andrea G, Terrazzino S, Fortin D, Farruggio A, Rinaldi L, Leon A (2003) HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amines receptors in circulating leukocytes. Neurosci Lett 346(1–2):89–92

    Article  PubMed  Google Scholar 

  33. D’Andrea G, Granella F, Perini F, Farruggio A, Leone M, Bussone G (2006) Platelet levels of dopamine are increased in migraine and cluster headache. Headache 46(4):585–591

    Article  PubMed  Google Scholar 

  34. Fernandez F, Lea RA, Colson NJ, Bellis C, Quinlan S, Griffits LR (2006) Association between a 19 bp deletion polymorphism at dopamine beta-hydroxylase (DBH) locus and migraine with aura. J Neurol Sci 251(1–2):118–123

    Article  CAS  PubMed  Google Scholar 

  35. Magos A, Brincat M, Zilkha KJ, Studd JW (1985) Serum dopamine b-hydroxylase activity in menstrual migraine. J Neurol Neurosurg Psychiatry 48(4):328–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gallai V, Gaiti A, Sarchielli P, Coata G, Trequattrini A, PaciaroniM, (1992) Evidence for an altered dopamine b-hydroxylase activity in migraine and tension type headache. Acta Neurol Scand 86:403–406

    Article  CAS  PubMed  Google Scholar 

  37. D’Andrea G, Cananzi AR, Morra M, Fornasiero S, Zamberlan F, Welch KMA et al (1989) Platelet as model to test autonomic function in migraine. Funct Neurol 4(1):79–84

    PubMed  Google Scholar 

  38. Martignoni F, Blandini F, D’Andrea G et al (1990) Platelet and plasma catecholamines in migraine patients. Evidences of menstrual-related variability of the noradrenergic tone. Biog Amines 10:227–237

    Google Scholar 

  39. Peres MFP, Sanchez del Rio M, Seabra MLV, Tufik S, Abucham J, Cipolla-Neto J, Siberstein SD, Zuckermann E (2007) Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry 71:747–751

    Article  Google Scholar 

  40. D’Andrea G, Hasselmark L, Cananzi AR, Alecci M, Perini F, Zamberlan F, Welch KMA (1995) Metabolism and menstrual cycle rhythmicity of serotonin in primary headaches. Headache 35(4):216–221

    Article  PubMed  Google Scholar 

  41. Fioroni L, D’Andrea G, Alecci M, Cananzi AR, Facchinetti F (1996) Platelet serotonin pathway in menstrual migraine. Cephalalgia 16(6):427–430

    Article  CAS  PubMed  Google Scholar 

  42. Casucci G, Villani V, Frediani F (2008) Central mechanism of action of antimigraine prophylactic drugs. Neurol Sci 29(Suppl1):S123–S126

    Article  PubMed  Google Scholar 

  43. Bigal ME, Hetherington H, Pan J, Tsang A et al (2008) Occipital levels of GABA are related to severe headaches in migraine. Neurology 70(22):2078–2080

    Article  CAS  PubMed  Google Scholar 

  44. Welch KMA, Chabi E, Nell JH, Bartosh K, Achar VS, Meyer JS (1975) Cerebrospinal fluid gamma aminobutyric acid levels and migraine. Br Med J 3(5882):516–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang SP, Pau KY, Spies HG (1997) Gonadectomy alters tyrosine hydroxylase and norepinephrine transporter mRNA levels in the locus coeruleus of the rabbit. J Neuroendocrinol 9(10):763–768

    Article  CAS  PubMed  Google Scholar 

  46. Virmani A, Gaetani F, Imam S, Binienda Z, Ali S (2002) The protective role of L-carnitine against neurotoxicity evoked by drug abuse, methamphetamine, could be related to mitochondrial dysfunction. Ann N Y Acad Sci 965:225–232

    Article  CAS  PubMed  Google Scholar 

  47. Balbi T, Fusco M, Vasapollo D, Boschetto R, Cocco P, Leon A, Farruggio A (2005) The presence of trace amines in postmortem cerebrospinal fluid in humans. J Forensic Sci 50(3):630–632

    Article  CAS  PubMed  Google Scholar 

  48. Welch KMA, Nagesh V, Aurora SK, Gelman N (2001) Periacqueductal gray matter dysfunction in migraine: cause or burden of illness? Headache 41:629–637

    Article  CAS  PubMed  Google Scholar 

  49. Welch KMA (2009) Iron in the migraine brain: a resilient hypothesis. Cephalalgia 29(3):283–285

    Article  CAS  PubMed  Google Scholar 

  50. Scher AI, Stewart WF, Ricci JA, Lipton RB (2003) Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 106:81–89

    Article  CAS  PubMed  Google Scholar 

  51. Katsarava Z, Schneeweiss S, Kurth T et al (2004) Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 62:788–790

    Article  CAS  PubMed  Google Scholar 

  52. D’Andrea G, D’Amico D, Bussone G, Bolner A et al (2013) The role of tyrosine metabolism in the pathogenesis of chronic migraine. Cephalalgia 33(11):932–937

    Article  PubMed  Google Scholar 

  53. Berry DB (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90:257–271

    Article  CAS  PubMed  Google Scholar 

  54. Anwar MA, Ford WR, Herbert AA et al (2013) Signal transduction and modulating pathways in tryptamine-evoked vasopressor responses of the rat isolated perfused mesenteric bed. Vasc Pharmacol 58:140–149

  55. D’Andrea G, D’Amico D, Bussone G, Bolner A et al (2014) Tryptamine levels are low in plasma of chronic migraine and chronic tension type headache. Neurol Sci 35:1941–1945

    Article  PubMed  Google Scholar 

  56. De Boer SF, Koolhass JM (2005) 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge on the serotonin deficiency hypothesis. Eur J Pharmaco 526(1–3):125–139

    Article  Google Scholar 

  57. Huo FQ, Huang FS, Lv BC et al (2010) Activation of serotonin in ventrolateral orbital cortex depresses persistent nociception: a presynaptic inhibition mechanism. Neurochem Int 57:749–755

    Article  CAS  PubMed  Google Scholar 

  58. Pockros AL, Pentkowski NS, Swinford SE et al (2011) Blockade of 5-HT2A in medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats. Psycopharmacologyù (Berl) 213(2–3):307–320

    Article  CAS  Google Scholar 

  59. QuGL Huo FQ, Huang FS et al (2008) The role of 5-HT receptor subtypes in the ventrolateral orbital cortex of 5-HT-induced antinociception in the rat. Neuroscience 152:487–494S22 Neurol Sci (2015) 36 (Suppl 1):S17–S22

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Correspondence to Giovanni D’Andrea.

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D’Andrea, G., Gucciardi, A. & Leon, A. Elusive amines: migraine depends on biochemical abnormalities. Neurol Sci 43, 6299–6304 (2022). https://doi.org/10.1007/s10072-022-06241-2

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