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Open Access 01-12-2013 | Review article

Genes and primary headaches: discovering new potential therapeutic targets

Authors: Innocenzo Rainero, Elisa Rubino, Koen Paemeleire, Annalisa Gai, Alessandro Vacca, Paola De Martino, Salvatore Gentile, Paola Sarchielli, Lorenzo Pinessi

Published in: The Journal of Headache and Pain | Issue 1/2013

Abstract

Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed.

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Headache Classification Subcommittee of the International Headache Society: The international classification of headache disorders: 2nd edn. Cephalalgia 2004,24(Suppl 1):9–160.

Lantéri-Minet M, Duru G, Mudge M, Cottrell S: Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia 2011,31(7):837–850. 10.1177/0333102411398400PubMedCrossRef

Raggi A, Giovannetti AM, Quintas R, D’Amico D, Cieza A, Sabariego C, Bickenbach JE, Leonardi M: A systematic review of the psychosocial difficulties relevant to patients with migraine. J Headache Pain 2012,13(8):595–606. 10.1007/s10194-012-0482-1PubMedCentralPubMedCrossRef

Pradalier A, Auray JP, El Hasnaoui A, Alzahouri K, Dartigues JF, Duru G, Henry P, Lantéri-Minet M, Lucas C, Chazot G, Gaudin AF: Economic impact of migraine and other episodic headaches in France: data from the GRIM2000 study. PharmacoEconomics 2004,22(15):985–999. 10.2165/00019053-200422150-00003PubMedCrossRef

Bloudek LM, Stokes M, Buse DC, Wilcox TK, Lipton RB, Goadsby PJ, Varon SF, Blumenfeld AM, Katsarava Z, Pascual J, Lanteri-Minet M, Cortelli P, Martelletti P: Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS). J Headache Pain 2012,13(5):361–378. 10.1007/s10194-012-0460-7PubMedCentralPubMedCrossRef

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al.: Years lived with disability (YLD) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systemati c analysis for the Global Burden of Disease Study 2010. Lancet 2012,380(9859):2163–2196. 10.1016/S0140-6736(12)61729-2PubMedCrossRef

Russell MB: Genetics in primary headaches. J Headache Pain 2007,8(3):190–195. 10.1007/s10194-007-0389-4PubMedCentralPubMedCrossRef

Svensson DA, Larsson B, Waldenlind E, Pedersen NL: Shared rearing environment in migraine: results from twins reared apart and twins reared together. Headache 2003,43(3):235–244. 10.1046/j.1526-4610.2003.03047.xPubMedCrossRef

Ophoff RA, Terwindt GM, Vergouwe MN, et al.: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996, 87: 543–552. 10.1016/S0092-8674(00)81373-2PubMedCrossRef

10.

De Fusco M, Marconi R, Silvestri L, et al.: Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003, 33: 192–196. 10.1038/ng1081PubMedCrossRef

11.

Dichgans M, Freilinger T, Eckstein G, et al.: Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005, 366: 371–377. 10.1016/S0140-6736(05)66786-4PubMedCrossRef

12.

Colson NJ, Lea RA, Quinlan S, Griffiths LR: The role of vascular and hormonal genes in migraine susceptibility. Mol Genet Metab 2006, 88: 107–113. 10.1016/j.ymgme.2005.11.013PubMedCrossRef

13.

Maher BH, Griffiths LR: Identification of molecular genetic factors that influence migraine. Mol Genet Genomics 2011,285(6):433–446. 10.1007/s00438-011-0622-3PubMedCrossRef

14.

Vanmolkot FH, Van Bortel LM, de Hoon JN: Altered arterial function in migraine of recent onset. Neurology 2007,68(19):1563–1570. 10.1212/01.wnl.0000260964.28393.edPubMedCrossRef

15.

Barriga FJ, Cuadrado ML, Bueno A, Barón M, Dobato JL, Vela L, Pareja JA: Clus ter headache: orbital hemodynamic changes during Valsalva maneuver. Headache 2006,46(2):298–305. 10.1111/j.1526-4610.2006.00287.xPubMedCrossRef

16.

Kurth T: The association of migraine with ischemic stroke. Curr Neurol Neurosci Rep 2010,10(2):133–139. 10.1007/s11910-010-0098-2PubMedCrossRef

17.

Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE: Migraine and risk of cardiovascular disease in women. JAMA 2006,296(3):283–291. 10.1001/jama.296.3.283PubMedCrossRef

18.

Sacco S, Ricci S, Carolei A: Migraine and vascular diseases: a review of the evidence and potential implications for management. Cephalalgia 2012,32(10):785–795. 10.1177/0333102412451361PubMedCrossRef

19.

Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alpérovitch A: Association between migraine and endothelin type A receptor (ETA −231 A/G) gene polymorphism. Neurology 2001,56(10):1273–1277. 10.1212/WNL.56.10.1273PubMedCrossRef

20.

Tronvik E, Stovner LJ, Schrader H, Bovim G: Involvement of the renin-angiotensin system in migraine. J Hypertens 2006, 24: 139–143. 10.1097/01.hjh.0000220419.86149.11CrossRef

21.

Rubino E, Fenoglio P, Gallone S, Govone F, Vacca A, De Martino P, Giobbe ML, Boschi S, Pinessi L, Gentile S, Rainero I: Genetic variants in the NOTCH4 gene influence the clinical features of migraine. J Headache Pain 2013,14(1):28. 10.1186/1129-2377-14-28PubMedCentralPubMedCrossRef

22.

Scher AI, Terwindt GM, Verschuren WM, Kruit MC, Blom HJ, Kowa H, Frants RR, van den Maagdenberg AM, van Buchem M, Ferrari MD, Launer LJ: Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 2006,59(2):372–375. 10.1002/ana.20755PubMedCrossRef

23.

Liu A, Menon S, Colson NJ, Quinlan S, Cox H, Peterson M, Tiang T, Haupt LM, Lea RA, Griffiths LR: Analysis of the MTHFR C677T variant with migraine phenotypes. BMC Res Notes 2010, 3: 213. 10.1186/1756-0500-3-213PubMedCentralPubMedCrossRef

24.

Samaan Z, Gaysina D, Cohen-Woods S, Craddock N, Jones L, Korszun A, Owen M, Mente A, McGuffin P, Farmer A: Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol 2011, 11: 66. 10.1186/1471-2377-11-66PubMedCentralPubMedCrossRef

25.

McCully KS: Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci 2009,39(3):219–232.PubMed

26.

Dionisio N, Jardín I, Salido GM, Rosado JA: Homocysteine, intracellular signaling and thrombotic disorders. Curr Med Chem 2010,17(27):3109–3119. 10.2174/092986710791959783PubMedCrossRef

27.

Boldyrev A, Bryushkova E, Mashkina A, Vladychenskaya E: Why is Homocysteine toxic for the nervous and immune systems? Curr Aging Sci 2012. [Epub ahead of print]

28.

Zieminska E, Lazarewicz JW: Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vitro: the role of NMDA and group I metabotropic glutamate receptors. Acta Neurobiol Exp (Wars) 2006,66(4):301–309.

29.

Yeganeh F, Nikbakht F, Bahmanpour S, Rastegar K, Namavar R: Neuroprotective effects of NMDA and Group I metabotropic glutamate receptor antagonists against neurodegeneration induced by homocysteine in rat hippocampus: in vivo study. J Mol Neurosci 2013. [Epub ahead of print]

30.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995,10(1):111–113. 10.1038/ng0595-111PubMedCrossRef

31.

Trabetti E: Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. J Appl Genet 2008,49(3):267–282. 10.1007/BF03195624PubMedCrossRef

32.

Pizza V, Bisogno A, Lamaida E, Agresta A, Bandieramonte G, Volpe A, Galasso R, Galasso L, Caputo M, Tecce MF, Capasso A: Migraine and coronary artery disease: an open study on the genetic polymorphism of the 5, 10 methylenetetrahydrofolate (MTHFR) and angiotensin I-converting enzyme (ACE) genes. Cent Nerv Syst Agents Med Chem 2010,10(2):91–96. 10.2174/187152410791196404PubMedCrossRef

33.

Sazci A, Ergul E, Tuncer N, Akpinar G, Kara I: Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: dual effect of MTHFR polymorphisms C677T and A1298C. Brain Res Bull 2006,71(1–3):45–50.PubMedCrossRef

34.

Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L: Homocysteine and depression in later life. Arch Gen Psychiatry 2008,65(11):1286–1294. 10.1001/archpsyc.65.11.1286PubMedCrossRef

35.

Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L, de Hert M, Delespaul P, van Winkel R, Rutten BP, MTHFR in Psychiatry Group: Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 2011,25(8):1530–1543. 10.1016/j.bbi.2010.12.006PubMedCrossRef

36.

Rubino E, Ferrero M, Rainero I, Binello E, Vaula G, Pinessi L: Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis. Cephalalgia 2009, 8: 818–825.CrossRef

37.

Schürks M, Rist PM, Kurth T: MTHFR 677C>T and ACE D/I polymorphisms in migraine: a systematic review and meta-analysis. Headache 2010,50(4):588–599. 10.1111/j.1526-4610.2009.01570.xPubMedCentralPubMedCrossRef

38.

Schürks M, Neumann FA, Kessler C, Diener HC, Kroemer HK, Kurth T, Völzke H, Rosskopf D: MTHFR 677C>T polymorphism and cluster headache. Headache 2010,51(2):201–207.PubMedCrossRef

39.

Moschiano F, D’Amico D, Usai S, Grazzi L, Di Stefano M, Ciusani E, Erba N, Bussone G: Homocysteine plasma levels in patients with migraine with aura. Neurol Sci 2008,29(Suppl 1):S173-S175.PubMedCrossRef

40.

Lea R, Colson N, Quinlan S, Macmillan J, Griffiths L: The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenet Genomics 2009,19(6):422–428. 10.1097/FPC.0b013e32832af5a3PubMedCrossRef

41.

Menon S, Lea RA, Roy B, Hanna M, Wee S, Haupt LM, Oliver C, Griffiths LR: Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation. Pharmacogenet Genomics 2012,22(10):741–749. 10.1097/FPC.0b013e3283576b6bPubMedCrossRef

42.

Miao J, Wang F, Fang Y: Association of 231G>A polymorphism of endothelin type A receptor gene with migraine: a meta-analysis. J Neurol Sci 2012,323(1–2):232–235.PubMedCrossRef

43.

Haigh S, Karanovic O, Wilkinson F, Wilkins A: Cortical hyperexcitability in migraine and aversion to patterns. Cephalalgia 2012,32(3):236–240. 10.1177/0333102411433301PubMedCentralPubMedCrossRef

44.

Coppola G, Pierelli F, Schoenen J: Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 2007,27(12):1427–1439. 10.1111/j.1468-2982.2007.01500.xPubMedCrossRef

45.

Ferrari MD, van der Maagdenberg AM, Frants RR, Goadsby PJ: Migraine as a cerebral ionopathy with impaired central sensory processing. In Molecular Neurology. Edited by: Waxman SG. Amsterdam: Elsevier; 2007:439–461.CrossRef

46.

Eikermann-Haerter K, Yuzawa I, Qin T, Wang Y, Baek K, Kim YR, Hoffmann U, Dilekoz E, Waeber C, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C: Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice. J Neurosci 2011,31(15):5755–5763. 10.1523/JNEUROSCI.5346-10.2011PubMedCentralPubMedCrossRef

47.

Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, Pizzorusso T, Casari G: Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet 2012,7(6):e1002129. 10.1371/journal.pgen.1002129CrossRef

48.

Bianchin MM, Londero RG, Lima JE, Bigal ME: Migraine and epilepsy: a focus on overlapping clinical, pathophysiological, molecular, and therapeutic aspects. Curr Pain Headache Rep 2010,14(4):276–283. 10.1007/s11916-010-0121-yPubMedCrossRef

49.

Striano P, Belcastro V, Verrotti A, Parisi P: “Comorbidity” between epilepsy and headache/migraine: the other side of the same coin! J Headache Pain 2011,12(5):577–578. 10.1007/s10194-011-0371-zPubMedCentralPubMedCrossRef

50.

Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, McLaughlan S, Dubé MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA: A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 2010,16(10):1157–1160. 10.1038/nm.2216PubMedCrossRef

51.

Egenberger B, Polleichtner G, Wischmeyer E, Döring F: N-linked glycos ylation determines cell surface expression of two-pore-domain K+ channel TRESK. Biochem Biophys Res Commun 2010,391(2):1262–1267. 10.1016/j.bbrc.2009.12.056PubMedCrossRef

52.

Kang D, Mariash E, Kim D: Functional expression of TRESK-2, a new member of the tandem-pore K+ channel family. J Biol Chem 2004,279(27):28063–28070. 10.1074/jbc.M402940200PubMedCrossRef

53.

Li H, Rao A, Hogan PG: Structural delineation of the calcineurin–NFAT inte raction and its parallels to PP1 targeting interactions. J Mol Biol 2004,342(5):1659–1674. 10.1016/j.jmb.2004.07.068PubMedCrossRef

54.

Enyedi P, Braun G, Czirják G: TRESK: the lone ranger of two-pore domain potassium channels. Mol Cell Endocrinol 2012,353(1–2):75–81.PubMedCrossRef

55.

Dobler T, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E, Döring F: TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J Physiol 2007,585(Pt 3):867–879.PubMedCentralPubMedCrossRef

56.

Huang DY, Yu BW, Fan QW: Roles of TRESK, a novel two-pore domain K+ channel, in pain pathway and general anesthesia. Neurosci Bull 2008,24(3):166–172. 10.1007/s12264-008-0225-0PubMedCrossRef

57.

Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafrenière RG, Roy B, Griffiths LR, Rouleau GA, Ebers GC, Cader ZM, Tucker SJ: Functional analysis of missense variants in the TRESK (KCNK18) K channel. Sci Rep 2012, 2: 237–240.PubMedCentralPubMedCrossRef

58.

Rainero I, Rubino E, Fenoglio P, Gallone S, Zavarise P, Carli D, Boschi S, Gai A, Pinessi L, Dalla Volta G: Investigation of KCNK18 (TRESK) Genetic Variants in Migraine with and without Aura. In: Abstracts of the 65th AAN Annual Meeting, San Diego. Neurology 2013,80(Meeting Abstracts 1):S55.003.

59.

Marsh B, Acosta C, Djouhri L, Lawson SN: Leak K⁺ channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behaviour. Mol Cell Neurosci 2012,49(3):375–386. 10.1016/j.mcn.2012.01.002PubMedCrossRef

60.

Tulleuda A, Cokic B, Callejo G, Saiani B, Serra J, Gasull X: TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury. Mol Pain 2011, 7: 30. 10.1186/1744-8069-7-30PubMedCentralPubMedCrossRef

61.

Nassini R, De Cesaris F, Pedretti P, Geppetti P: TRPS and migraine. The Open Drug Discovery Journal 2010, 2: 55–63. 10.2174/1877381801002030055CrossRef

62.

Oxford GS, Hurley JH: The role of TRP channels in migraine. The Open Pain Journal 2013,6(Suppl 1):37–49.CrossRef

63.

Vennekens R, Menigoz A, Nilius B: TRPs in the Brain. Rev Physiol Biochem Pharmacol 2012, 163: 27–64.PubMed

64.

Bae YC, Oh JM, Hwang SJ, Shigenaga Y, Valtschanoff JG: Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei. J Comp Neurol 2004,478(1):62–71. 10.1002/cne.20272PubMedCrossRef

65.

Meents JE, Neeb L, Reuter U: TRPV1 in migraine pathophysiology. Trends Mol Med 2010,16(4):153–159. 10.1016/j.molmed.2010.02.004PubMedCrossRef

66.

Carreño O, Corominas R, Fernández-Morales J, Camiña M, Sobrido MJ, Fernández-Fernández JM, Pozo-Rosich P, Cormand B, Macaya A: SNP variants within the vanilloid TRPV1 and TRPV3 receptor genes are associated with migraine in the Spanish population. Am J Med Genet B Neuropsychiatr Genet 2012,159B(1):94–103. 10.1002/ajmg.b.32007PubMedCrossRef

67.

Chasman DI, Schürks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den Maagdenberg AM, Fendrich K, Völzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T: Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 2011,43(7):695–698. 10.1038/ng.856PubMedCentralPubMedCrossRef

68.

Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Vila-Pueyo M, Göbel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, et al.: Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet 2012,44(7):777–782. 10.1038/ng.2307PubMedCentralPubMedCrossRef

69.

Lambert GA, Davis JB, Appleby JM, Chizh BA, Hoskin KL, Zagami AS: The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission. Naunyn Schmiedebergs Arch Pharmacol 2009,380(4):311–325. 10.1007/s00210-009-0437-5PubMedCrossRef

70.

Szallasi A, Cruz F, Geppetti P: RPV1: a therapeutic target for novel analgesic drugs? Trends Mol Med 2006,12(11):545–554. 10.1016/j.molmed.2006.09.001PubMedCrossRef

71.

Silberstein SD: The role of sex hormones in headache. Neurology 1992,42(Suppl 2):37–42.PubMed

72.

Nappi RE, Nappi G: Neuroendocrine aspects of migraine in women. Gynecol Endocrinol 2012,28(Suppl 1):37–41.PubMedCrossRef

73.

Alstadhaug KB: Migraine and the hypothalamus. Cephalalgia 2009,29(8):809–817. 10.1111/j.1468-2982.2008.01814.xPubMedCrossRef

74.

Schürks M, Rist PM, Kurth T: Sex hormone receptor gene polymorphisms and migrain e: a systematic review and meta-analysis. Cephalalgia 2010, 11: 1306–1328.CrossRef

75.

Joshi G, Pradhan S, Mittal B: Role of the oestrogen receptor (ESR1 PvuII and ESR1 325 C->G) and progesterone receptor (PROGINS) polymorphisms in genetic susceptibility to migraine in a North Indian population. Cephalalgia 2010,30(3):311–320.PubMed

76.

De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG: The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998,95(1):322–327. 10.1073/pnas.95.1.322PubMedCentralPubMedCrossRef

77.

Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M: Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998,92(4):573–585. 10.1016/S0092-8674(00)80949-6PubMedCrossRef

78.

Rainero I, De Martino P, Pinessi L: Hypocretins and primary headaches: neurobiology and clinical implications. Expert Rev Neurother 2008,8(3):409–416. 10.1586/14737175.8.3.409PubMedCrossRef

79.

Nishino S: The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides 2007,41(3):117–133. 10.1016/j.npep.2007.01.003PubMedCrossRef

80.

Mori T, Ito S, Kuwaki T, Yanagisawa M, Sakurai T, Sawaguchi T: Monoaminergic neuronal changes in orexin deficient mice. Neuropharmacology 2012,58(4–5):826–832.

81.

Girault EM, Yi CX, Fliers E, Kalsbeek A: Orexins, feeding, and energy balance. Prog Brain Res 2012, 198: 47–64.PubMedCrossRef

82.

Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G: Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 2012, 198: 79–121.PubMedCentralPubMedCrossRef

83.

Yamamoto T, Saito O, Shono K, Aoe T, Chiba T: Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model. Neurosci Lett 2003,347(3):183–186. 10.1016/S0304-3940(03)00716-XPubMedCrossRef

84.

Rainero I, Gallone S, Valfrè W, Ferrero M, Angilella G, Rivoiro C, Rubino E, De Martino P, Savi L, Ferrone M, Pinessi L: A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 2004,63(7):1286–1288. 10.1212/01.WNL.0000142424.65251.DBPubMedCrossRef

85.

Schürks M, Kurth T, Geissler I, Tessmann G, Diener HC, Rosskopf D: Cluster heada che is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 2006,66(12):1917–1919. 10.1212/01.wnl.0000215852.35329.34PubMedCrossRef

86.

Baumber L, Sjöstrand C, Leone M, Harty H, Bussone G, Hillert J, Trembath RC, MB R e: A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 2006,66(12):1888–1893. 10.1212/01.wnl.0000219765.95038.d7PubMedCrossRef

87.

Rainero I, Rubino E, Valfrè W, Gallone S, De Martino P, Zampella E, Pinessi L: Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis. J Headache Pain 2007,8(3):152–156. 10.1007/s10194-007-0383-xPubMedCentralPubMedCrossRef

88.

Pinessi L, Binello E, De Martino P, Gallone S, Gentile S, Rainero I, Rivoiro C, Rubino E, Savi L, Valfrè W, Vaula G: The 1246G–>A polymorphism of the HCRTR2 gene is not associated with migraine. Cephalalgia 2007,27(8):945–949. 10.1111/j.1468-2982.2007.01347.xPubMedCrossRef

89.

Schürks M, Limmroth V, Geissler I, Tessmann G, Savidou I, Engelbergs J, Kurth T, Di ener HC, Rosskopf D: Association between migraine and the G1246A polymorphism in the hypocretin receptor 2 gene. Headache 2007,47(8):1195–1199. 10.1111/j.1526-4610.2007.00863.xPubMedCrossRef

90.

Rainero I, Rubino E, Gallone S, Fenoglio P, Picci LR, Giobbe L, Ostacoli L, Pinessi L: Evidence for an association between migraine and the hypocretin receptor 1 gene. J Headache Pain 2011,12(2):193–199. 10.1007/s10194-011-0314-8PubMedCentralPubMedCrossRef

91.

Inutsuka A, Yamanaka A: The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 2013, 4: 18.

92.

Mang GM, Dürst T, Bürki H, Imobersteg S, Abramowski D, Schuepbach E, Hoyer D, F endt M, Gee CE: The dual orexin receptor antagonist almorexant induces sleep and decreases orexin- induced locomotion by blocking orexin 2 receptors. Sleep 2012,35(12):1625–1635.PubMedCentralPubMed

93.

Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM: Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 2013,36(2):259–267.PubMedCentralPubMed

94.

Mieda M, Sakurai T: Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. CNS Drugs 2013,27(2):83–90. 10.1007/s40263-012-0036-8PubMedCrossRef

95.

Zhou L, Ghee SM, Chan C, Lin L, Cameron MD, Kenny PJ, See RE: Orexin-1 receptor mediation of cocaine seeking in male and female rats. J Pharmacol Exp Ther 2012,340(3):801–809. 10.1124/jpet.111.187567PubMedCentralPubMedCrossRef

Title: Genes and primary headaches: discovering new potential therapeutic targets
Authors: Innocenzo Rainero
Elisa Rubino
Koen Paemeleire
Annalisa Gai
Alessandro Vacca
Paola De Martino
Salvatore Gentile
Paola Sarchielli
Lorenzo Pinessi
Publication date: 01-12-2013
Publisher: Springer Milan
Published in: The Journal of Headache and Pain / Issue 1/2013
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/1129-2377-14-61

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genes and primary headaches: discovering new potential therapeutic targets

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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