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Review

Orexins and primary headaches: an overview of the neurobiology and clinical impact

ORCID Icon, ORCID Icon & ORCID Icon
Pages 487-496 | Received 19 Dec 2023, Accepted 19 Feb 2024, Published online: 22 Mar 2024

References

  • Kopel D, Gottschalk C. The epidemiology of primary headache disorders. Semin Neurol. 2022;42(4):449–458. doi: 10.1055/a-1942-6823
  • Onofri A, Pensato U, Rosignoli C, et al. Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis. J Headache Pain. 2023;24(1):8. doi: 10.1186/s10194-023-01541-0
  • Lipton RB, Liberman JN, Kolodner KB, et al. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia. 2003;23(6):441–450. doi: 10.1046/j.1468-2982.2003.00546.x
  • Abu Bakar N, Tanprawate S, Lambru G, et al. Quality of life in primary headache disorders: a review. Cephalalgia. 2016;36(1):67–91. doi: 10.1177/0333102415580099
  • Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. doi: 10.1177/0333102417738202
  • Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med. 2007;13(1):39–44. doi: 10.1016/j.molmed.2006.11.005
  • Goadsby PJ. Primary headache disorders: five new things. Neurol Clin Pract. 2019;9(3):233–240. doi: 10.1212/CPJ.0000000000000654
  • Buture A, Boland JW, Dikomitis L, et al. Update on the pathophysiology of cluster headache: imaging and neuropeptide studies. J Pain Res. 2019;12:269–281. doi: 10.2147/JPR.S175312
  • Khan J, Asoom LIA, Sunni AA, et al. Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. Biomed Pharmacother. 2021;139:111557. doi: 10.1016/j.biopha.2021.111557
  • Brandt RB, Doesborg PGG, Haan J, et al. Pharmacotherapy for cluster headache. CNS Drugs. 2020;34(2):171–184. doi: 10.1007/s40263-019-00696-2
  • Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ Emerging targets for migraine treatment. Neurol India. 2021;69:98. 7 10.4103/0028-3886.315989
  • Strother LC, Srikiatkhachorn A, Supronsinchai W. Targeted orexin and hypothalamic neuropeptides for migraine. Neurotherapeutics. 2018;15(2):377–390. doi: 10.1007/s13311-017-0602-3
  • Saper CB, Lowell BB. The hypothalamus. Curr Biol. 2014;24(23):R1111–R1116. doi: 10.1016/j.cub.2014.10.023
  • Montagna P. Hypothalamus, sleep and headaches. Neurol Sci. 2006;27(S2):s138–s143. doi: 10.1007/s10072-006-0589-8
  • Schulte LH, Allers A, May A. Hypothalamus as a mediator of chronic migraine: evidence from high-resolution fMRI. Neurology. 2017;88(21):2011–2016. doi: 10.1212/WNL.0000000000003963
  • Denuelle M, Fabre N, Payoux P, et al. Hypothalamic activation in spontaneous migraine attacks. Headache. 2007;47(10):1418–1426. doi: 10.1111/j.1526-4610.2007.00776.x
  • Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137(1):232–241. doi: 10.1093/brain/awt320
  • Sprenger T, Boecker H, Tolle TR, et al. Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology. 2004;62(3):516–517. doi: 10.1212/WNL.62.3.516
  • Moulton EA, Becerra L, Johnson A, et al. Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in Migraine. PloS One. 2014;9(4):e95508. doi: 10.1371/journal.pone.0095508
  • Lerebours F, Boulanouar K, Barège M, et al. Functional connectivity of hypothalamus in chronic migraine with medication overuse. Cephalalgia. 2019;39(7):892–899. doi: 10.1177/0333102419833087
  • Meylakh N, Marciszewski KK, Di Pietro F, et al. Altered regional cerebral blood flow and hypothalamic connectivity immediately prior to a migraine headache. Cephalalgia. 2020;40(5):448–460. doi: 10.1177/0333102420911623
  • Messina R, Rocca MA, Valsasina P, et al. 2022 Clinical correlates of hypothalamic functional changes in migraine patients [internet]. [cited 2023 May 17]. Available from: https://journals.sagepub.com/doi/full/10.1177/03331024211046618.
  • Coppola G, Di Renzo A, Petolicchio B, et al. Increased neural connectivity between the hypothalamus and cortical resting-state functional networks in chronic migraine. J Neurol. 2020;267(1):185–191. doi: 10.1007/s00415-019-09571-y
  • Benkli B, Kim SY, Koike N, et al. Circadian features of cluster headache and migraine: a systematic review, meta-analysis, and genetic analysis. Neurology. 2023;100(22):e2224–e2236. doi: 10.1212/WNL.0000000000207240
  • Stanyer EC, Brookes J, Pang JR, et al. Investigating the relationship between sleep and migraine in a global sample: a Bayesian cross-sectional approach. J Headache Pain. 2023;24(1):123. doi: 10.1186/s10194-023-01638-6
  • Engstrøm M, Hagen K, Bjørk M, et al. Sleep-related and non-sleep-related migraine: interictal sleep quality, arousals and pain thresholds. J Headache Pain. 2013;14(1):68. doi: 10.1186/1129-2377-14-68
  • Dexter JD. The relationship between stage III + IV + REM sleep and arousals with Migraine. Headache. 1979;19(7):364–369. doi: 10.1111/j.1526-4610.1979.hed1907364.x
  • Dexter JD, Riley TL. Studies in Nocturnal migraine. Headache. 1975;15(1):51–62. doi: 10.1111/j.1526-4610.1975.hed1501051.x
  • Barloese M, Lund N, Petersen A, et al. Sleep and chronobiology in cluster headache. Cephalalgia. 2015;35(11):969–978. doi: 10.1177/0333102414564892
  • Stanyer EC, Creeney H, Nesbitt AD, et al. Subjective sleep quality and sleep architecture in patients with migraine: a meta-analysis. Neurology [Internet]. 2021 [cited 2021 Sep 24;97 16. doi: 10.1212/WNL.0000000000012701
  • Karsan N, Goadsby PJ. Biological insights from the premonitory symptoms of migraine. Nat Rev Neurol. 2018;14(12):699–710. doi: 10.1038/s41582-018-0098-4
  • May A, Burstein R. Hypothalamic regulation of headache and migraine. Cephalalgia. 2019;39(13):1710–1719. doi: 10.1177/0333102419867280
  • van den Pol AN, Tsujimoto KL. Neurotransmitters of the hypothalamic suprachiasmatic nucleus: immunocytochemical analysis of 25 neuronal antigens. Neuroscience. 1985;15:1049–1086. doi: 10.1016/0306-4522(85)90254-4
  • Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache. 2007;47(6):951–962. doi: 10.1111/j.1526-4610.2007.00842.x
  • Holland PR The orexins and their involvement in the modulation of trigeminovascular nociceptive transmission [Internet] [ PhD Thesis]. UCL (University College London); 2006 [cited 2024 Feb 20]. Available from: https://discovery.ucl.ac.uk/id/eprint/1445638/.
  • Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–585. doi: 10.1016/S0092-8674(00)80949-6
  • Lang M, Söll RM, Dürrenberger F, et al. Structure−activity studies of orexin a and orexin B at the human orexin 1 and orexin 2 receptors led to orexin 2 receptor selective and orexin 1 receptor preferring ligands. J Med Chem. 2004;47(5):1153–1160. doi: 10.1021/jm030982t
  • de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Procs Nati Aca Scie. 1998;95:322–327.
  • Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25. doi: 10.1002/cne.1190
  • Marcus JN, Elmquist JK. Orexin projections and localization of orexin receptors. In: Nishino S Sakurai T editors. The Orexin/Hypocretin System: physiology and pathophysiology [internet]. Totowa (NJ): Humana Press; 2005 [cited 2023 May 16]p. 21–43. Available from. doi: 10.1385/1-59259-950-8:21
  • Thorpe AJ, Kotz CM. Orexin a in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res. 2005;1050(1–2):156–162. doi: 10.1016/j.brainres.2005.05.045
  • Hervieu GJ, Cluderay JE, Harrison DC, et al. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience. 2001;103(3):777–797. doi: 10.1016/S0306-4522(01)00033-1
  • Kirouac GJ, Parsons MP, Li S. Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus. Brain Res. 2005;1059(2):179–188. doi: 10.1016/j.brainres.2005.08.035
  • Stoyanova II, Lazarov NE. Localization of orexin-A-immunoreactive fibers in the mesencephalic trigeminal nucleus of the rat. Brain Res. 2005;1054:82–87. doi: 10.1016/j.brainres.2005.06.066
  • Peyron C, Tighe DK, van den AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996–10015. 23. doi: 10.1523/JNEUROSCI.18-23-09996.1998
  • Rosin DL, Weston MC, Sevigny CP, et al. Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J Comp Neurol. 2003;465(4):593–603. doi: 10.1002/cne.10860
  • Chou TC, Lee CE, Lu J, et al. Orexin (hypocretin) neurons contain dynorphin. J Neurosci. 2001;21(19):RC168–RC168. doi: 10.1523/JNEUROSCI.21-19-j0003.2001
  • Trivedi P, Yu H, MacNeil DJ, et al. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 1998;438(1–2):71–75. doi: 10.1016/S0014-5793(98)01266-6
  • Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–181. doi: 10.1038/nrn2092
  • Ferguson AV, Samson WK. The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol. 2003;24(3):141–150. doi: 10.1016/S0091-3022(03)00028-1
  • Aston-Jones G, Smith RJ, Moorman DE, et al. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology. 2009;56:112–121. doi: 10.1016/j.neuropharm.2008.06.060
  • Sargin D. The role of the orexin system in stress response. Neuropharmacology. 2019;154:68–78. doi: 10.1016/j.neuropharm.2018.09.034
  • Sakurai T. Orexins and orexin receptors: implication in feeding behavior. Regul Pept. 1999;85(1):25–30. doi: 10.1016/S0167-0115(99)00076-2
  • Inutsuka A, Yamashita A, Chowdhury S, et al. The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation. Sci Rep. 2016;6(1):1–15. doi: 10.1038/srep29480
  • Sureda Gibert P Investigating the migraine premonitory phase: neural networks regulating migraine initiation [Internet] [PhD Thesis]KCL (King’s College London); 2022 [cited 2024 Feb 20] Available from: https://kclpure.kcl.ac.uk/ws/portalfiles/portal/249095126/2022_Sureda_Gibert_1309897_ethesis.pdf.
  • Gerashchenko D, Kohls MD, Greco M, et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci. 2001;21(18):7273–7283. doi: 10.1523/JNEUROSCI.21-18-07273.2001
  • Levitt DR, Teitelbaum P Somnolence, akinesia, and sensory activation of motivated behavior in the lateral hypothalamic syndrome. Procs Nati Aca Scie. 1975;72:2819–2823.
  • Alexandre C, Andermann ML, Scammell TE. Control of arousal by the orexin neurons. Curr Opin Neurobiol. 2013;23(5):752–759. doi: 10.1016/j.conb.2013.04.008
  • De Luca R, Nardone S, Grace KP, et al. Orexin neurons inhibit sleep to promote arousal. Nat Commun. 2022;13(1):4163. doi: 10.1038/s41467-022-31591-y
  • Matsuki T, Takasu M, Hirose Y, et al. GABAA receptor-mediated input change on orexin neurons following sleep deprivation in mice. Neuroscience. 2015;284:217–224. doi: 10.1016/j.neuroscience.2014.09.063
  • Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Procs Nati Aca Scie. 1999;96:10911–10916.
  • Yamanaka A, Tabuchi S, Tsunematsu T, et al. Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci. 2010;30(38):12642–12652. doi: 10.1523/JNEUROSCI.2120-10.2010
  • Coleman PJ, Gotter AL, Herring WJ, et al. The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol. 2017;57(1):509–533. doi: 10.1146/annurev-pharmtox-010716-104837
  • Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365–376. doi: 10.1016/S0092-8674(00)81965-0
  • Kornum BR, Knudsen S, Ollila HM, et al. Narcolepsy. Nat Rev Dis Primers. 2017;3(1):1–19. doi: 10.1038/nrdp.2016.100
  • Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–474. doi: 10.1016/S0896-6273(00)00058-1
  • Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6(9):991–997. doi: 10.1038/79690
  • Dahmen N, Kasten M, Wieczorek S, et al. Increased frequency of migraine in narcoleptic patients: a confirmatory study. Cephalalgia. 2003;23(1):14–19. doi: 10.1046/j.1468-2982.2003.00343.x
  • Yang C-P, Hsieh M-L, Chiang J-H, et al. Migraine and risk of narcolepsy in children: a nationwide longitudinal study. PloS One. 2017;12(12):e0189231. doi: 10.1371/journal.pone.0189231
  • Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron. 2003;38(5):715–730. doi: 10.1016/S0896-6273(03)00330-1
  • Kantor S, Mochizuki T, Janisiewicz AM, et al. Orexin neurons are necessary for the circadian control of REM sleep. Sleep. 2009;32(9):1127–1134. doi: 10.1093/sleep/32.9.1127
  • Akyildiz UO, Tezer FI, Koc G, et al. The REM-sleep-related characteristics of narcolepsy: a nation-wide multicenter study in Turkey, the REMCON study. Sleep Med. 2022;94:17–25. doi: 10.1016/j.sleep.2022.03.025
  • Zhang Y, Ren R, Yang L, et al. Polysomnographic nighttime features of narcolepsy: a systematic review and meta-analysis. Sleep Med Rev. 2021;58:101488. doi: 10.1016/j.smrv.2021.101488
  • Taheri S, Sunter D, Dakin C, et al. Diurnal variation in orexin a immunoreactivity and prepro-orexin mRNA in the rat central nervous system. Neurosci lett. 2000;279(2):109–112. doi: 10.1016/S0304-3940(99)00955-6
  • Grady SP, Nishino S, Czeisler CA, et al. Diurnal variation in CSF orexin-A in healthy male subjects. Sleep. 2006;29(3):295–297. doi: 10.1093/sleep/29.3.295
  • Kiyashchenko LI, Mileykovskiy BY, Maidment N, et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci. 2002;22(13):5282–5286. doi: 10.1523/JNEUROSCI.22-13-05282.2002
  • Estabrooke IV, McCarthy MT, Ko E, et al. Fos expression in orexin neurons varies with behavioral state. J Neurosci. 2001;21:1656–1662. 5 10.1523/JNEUROSCI.21-05-01656.2001
  • Kelman L. The triggers or precipitants of the acute migraine attack. Cephalalgia. 2007;27(5):394–402. doi: 10.1111/j.1468-2982.2007.01303.x
  • Pergolizzi JV, Magnusson P, LeQuang JA, et al. Exploring the connection between sleep and cluster headache: a narrative review. Pain Ther. 2020;9(2):359–371. doi: 10.1007/s40122-020-00172-6
  • Siemian JN, Borja CB, Sarsfield S, et al. Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area. Sci Rep. 2019;9(1):12026. doi: 10.1038/s41598-019-48537-y
  • Bingham S, Davey PT, Babbs AJ, et al. Orexin-A, an hypothalamic peptide with analgesic properties. Pain. 2001;92(1):81–90. doi: 10.1016/S0304-3959(00)00470-X
  • Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. Biomed Pharmacother. 2017;90:187–193. doi: 10.1016/j.biopha.2017.03.053
  • Holland PR, Goadsby PJ. Cluster headache, hypothalamus, and orexin. Current Science Inc. 2009;13(2):147–154. doi: 10.1007/s11916-009-0025-x
  • Lopez R, Young SL, Cox VC. Analgesia for formalin-induced pain by lateral hypothalamic stimulation. Brain Res. 1991;563(1–2):1–6. doi: 10.1016/0006-8993(91)91506-V
  • Aimone LD, Bauer CA, Gebhart GF. Brain-stem relays mediating stimulation-produced antinociception from the lateral hypothalamus in the rat. J Neurosci. 1988;8(7):2652–2663. doi: 10.1523/JNEUROSCI.08-07-02652.1988
  • Carstens E. Hypothalamic inhibition of rat dorsal horn neuronal responses to noxious skin heating. Pain. 1986;25(1):95–107. doi: 10.1016/0304-3959(86)90012-6
  • Millan MJ, Przewlocki R, Millan MH, et al. Evidence for a role of the ventro-medial posterior hypothalamus in nociceptive processes in the rat. Pharmacol Biochem Behav. 1983;18(6):901–907. doi: 10.1016/S0091-3057(83)80013-6
  • Behbehani MM, Park MR, Clement ME. Interactions between the lateral hypothalamus and the periaqueductal gray. J Neurosci. 1988;8(8):2780–2787. doi: 10.1523/JNEUROSCI.08-08-02780.1988
  • Kajiyama S, Kawamoto M, Shiraishi S, et al. Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model rats. Brain Res. 2005;1044(1):76–86. doi: 10.1016/j.brainres.2005.03.007
  • Yamamoto T, Saito O, Shono K, et al. 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. doi: 10.1016/S0304-3940(03)00716-X
  • Heidari-Oranjaghi N, Azhdari-Zarmehri H, Erami E, et al. Antagonism of orexin-1 receptors attenuates swim- and restraint stress-induced antinociceptive behaviors in formalin test. Pharmacol Biochem Behav. 2012;103(2):299–307. doi: 10.1016/j.pbb.2012.08.007
  • Yamamoto T, Nozaki-Taguchi N, Chiba T. Analgesic effect of intrathecally administered orexin-A in the rat formalin test and in the rat hot plate test. Br J Pharmacol. 2002;137(2):170–176. doi: 10.1038/sj.bjp.0704851
  • Mobarakeh JI, Takahashi K, Sakurada S, et al. Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin a and B (hypocretin-1 and -2) in mice. Peptides. 2005;26(5):767–777. doi: 10.1016/j.peptides.2005.01.001
  • Bartsch T, Levy MJ, Knight YE, et al. Differential modulation of nociceptive dural input to [hypocretin] orexin a and B receptor activation in the posterior hypothalamic area. Pain. 2004;109(3):367–378. doi: 10.1016/j.pain.2004.02.005
  • Holland PR, Akerman S, Goadsby PJ. Orexin 1 Receptor Activation Attenuates Neurogenic Dural Vasodilation in an Animal Model of Trigeminovascular Nociception. J Pharmacol Exp Ther. 2005;315(3):1380–1385. doi: 10.1124/jpet.105.090951
  • Supronsinchai W, Hoffmann J, Akerman S, et al. Assessing the quality of health-related quality of life measures. Cephalalgia. 2013;33(4):223–225. SAGE PUBLICATIONS LTD 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND. doi: 10.1177/0333102412468681
  • Ashina M, Hansen JM, Á Dunga BO, et al. Human models of migraine — short-term pain for long-term gain. Nat Rev Neurol. 2017;13:713–724. 12 10.1038/nrneurol.2017.137
  • Askari-Zahabi K, Abbasnejad M, Kooshki R, et al. The role of basolateral amygdala orexin 1 receptors on the modulation of pain and psychosocial deficits in nitroglycerin-induced migraine model in adult male rats. Korean J Pain. 2022;35(1):22–32. doi: 10.3344/kjp.2022.35.1.22
  • Kooshki R, Abbasnejad M, Esmaeili-Mahani S, et al. Activation orexin 1 receptors in the ventrolateral periaqueductal gray matter attenuate nitroglycerin-induced migraine attacks and calcitonin gene related peptide up-regulation in trigeminal nucleus caudalis of rats. Neuropharmacology. 2020;178:107981. doi: 10.1016/j.neuropharm.2020.107981
  • Pourrahimi AM, Abbasnejad M, Raoof M, et al. The involvement of orexin 1 and cannabinoid 1 receptors within the ventrolateral periaqueductal gray matter in the modulation of migraine-induced anxiety and social behavior deficits of rats. Peptides. 2021;146:170651. doi: 10.1016/j.peptides.2021.170651
  • Boss C, Roch C. Recent trends in orexin research—2010 to 2015. Bioorganic Med Chem Lett. 2015;25(15):2875–2887. doi: 10.1016/j.bmcl.2015.05.012
  • Sears RM, Fink AE, Wigestrand MB, et al. Orexin/Hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Procs Nati Aca Scie. 2013;110:20260–20265.
  • Baskin SM, Lipchik GL, Smitherman TA. Mood and anxiety disorders in chronic headache. Headache. 2006;46(s3):S76–S87. doi: 10.1111/j.1526-4610.2006.00559.x
  • Vila-Pueyo M, Strother LC, Kefel M, et al. Divergent influences of the locus coeruleus on migraine pathophysiology. Pain. 2019;160(2):385–394. doi: 10.1097/j.pain.0000000000001421
  • May A, Bahra A, Buchel C, et al. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55(9):1328–1335. doi: 10.1212/WNL.55.9.1328
  • May A, Bahra A, Büchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275–278. doi: 10.1016/S0140-6736(98)02470-2
  • Cevoli S, Pizza F, Grimaldi D, et al. Cerebrospinal fluid hypocretin-1 levels during the active period of cluster headache. Cephalalgia. 2011;31(8):973–976. doi: 10.1177/0333102411403634
  • Barloese M. Reduced CSF hypocretin-1 levels are associated. Goo. [cited 2023 May 17]. Available from 10.1177/0333102414562971.
  • Strittmatter M, Hamann GF, Grauer M, et al. Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache. Neuroreport. 1996;7(7):1229–1234. doi: 10.1097/00001756-199605170-00001
  • Rainero I, Gallone S, Valfrè W, et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology. 2004;63(7):1286–1288. doi: 10.1212/01.WNL.0000142424.65251.DB
  • Schurks M, Kurth T, Geissler I, et al. Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology. 2006;66(12):1917–1919. doi: 10.1212/01.wnl.0000215852.35329.34
  • Rainero I, Gallone S, Rubino E, et al. Haplotype Analysis Confirms the Association between the HCRTR2 gene and cluster headache. Headache. 2008;48(7):1108–1114. doi: 10.1111/j.1526-4610.2008.01080.x
  • Baumber L, Sjostrand C, Leone M, et al. A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology. 2006;66(12):1888–1893. doi: 10.1212/01.wnl.0000219765.95038.d7
  • Schürks M, Kurth T, Geissler I, et al. The G1246A Polymorphism in the hypocretin receptor 2 gene is not associated with treatment response in cluster headache. Cephalalgia. 2007;27(4):363–367. doi: 10.1111/j.1468-2982.2007.01287.x
  • Burish MJ, Han C, Mawatari K, et al. The first-line cluster headache medication verapamil alters the circadian period and elicits sex-specific sleep changes in mice. Chronobiol Int. 2021;38(6):839–850. doi: 10.1080/07420528.2021.1892127
  • Cevoli S, Mochi M, Pierangeli G, et al. Investigation of the T3111C CLOCK gene polymorphism in cluster headache. J Neurol. 2008;255(2):299–300. doi: 10.1007/s00415-008-0719-8
  • Hirano A, Hsu P-K, Zhang L, et al. DEC2 modulates orexin expression and regulates sleep. Proc Natl Acad Sci, USA. 2018;115(13):3434. doi: 10.1073/pnas.1801693115
  • Barloese MCJ, Jennum PJ, Lund NT, et al. Sleep in cluster headache − beyond a temporal rapid eye movement relationship? Eur J Neurol. 2015;22(4):656–e40. doi: 10.1111/ene.12623
  • Marca GD, Vollono C, Rubino M, et al. Dysfunction of arousal systems in sleep-related migraine without aura. 2006;26(7): 857–64. doi: 10.1046/j.1468-2982.2002.00350.x-i1
  • Zaremba S, Holle D, Wessendorf TE, et al. Cluster headache shows no association with rapid eye movement sleep. Cephalalgia. 2012;32(4):289–296. doi: 10.1177/0333102411436332
  • Feng H, Wen S-Y, Qiao Q-C, et al. Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep. Nat Commun. 2020;11(1):3661. doi: 10.1038/s41467-020-17401-3
  • Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139(7):1987–1993. doi: 10.1093/brain/aww097
  • Leso V, Gervetti P, Mauro S, et al. Shift work and migraine: a systematic review. J Occup Health. 2020;62(1):e12116. doi: 10.1002/1348-9585.12116
  • Kelman L, Rains JC. Headache and sleep: examination of sleep patterns and complaints in a large clinical sample of migraineurs. Headache. 2005;45(7):904–910. doi: 10.1111/j.1526-4610.2005.05159.x
  • Kumar H, Dhamija K, Duggal A, et al. Fatigue, chronic fatigue syndrome and migraine: intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine. J Neurosci Rural Pract. 2023;14:424–431. doi: 10.25259/JNRP_63_2022
  • Brennan KC, Bates EA, Shapiro RE, et al. Casein Kinase Iδ Mutations in familial migraine and advanced sleep phase. Sci, trans med. 2013;5(183):183ra56. doi: 10.1126/scitranslmed.3005784
  • Sarchielli P, Rainero I, Coppola F, et al. Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and Medication-Overuse Headache: findings from cerebrospinal fluid. Cephalalgia. 2008;28(7):714–722. doi: 10.1111/j.1468-2982.2008.01566.x
  • Özaydin göksu E, Özaydin göksu S, Ünal A, et al. Orexin-A levels in episodic and chronic migraine: implications for hypothalamic involvement? J Neurol Sci. 2016;33:56–63.
  • Pinessi L, Binello E, Martino PD, et al. The 1246 G/A polymorphism of the HCRTR2 gene is not associated with migraine. Cephalalgia. 2007;27(8):945–949. doi: 10.1111/j.1468-2982.2007.01347.x
  • Schürks M, Limmroth V, Geissler I, et al. Association between migraine and the G1246A Polymorphism in the hypocretin receptor 2 gene. Headache. 2007;47(8):1195–1199. doi: 10.1111/j.1526-4610.2007.00863.x
  • Rainero I, Rubino E, Gallone S, et al. Evidence for an association between migraine and the hypocretin receptor 1 gene. J Headache Pain. 2011;12(2):193–199. doi: 10.1007/s10194-011-0314-8
  • Kowalska M, Kapelusiak-Pielok M, Grzelak T, et al. The new *G29A and G1222A of HCRTR1, 5-HTTLPR of SLC6A4 polymorphisms and hypocretin-1, serotonin concentrations in migraine patients. Front Mole Neurosci [Internet]. 2018;11 [cited 2023 May 18]. Available from: https://www.frontiersin.org/articles/10.3389/fnmol.2018.00191
  • Watanabe S, Kuwaki T, Yanagisawa M, et al. Persistent pain and stress activate pain-inhibitory orexin pathways. Neuroreport. 2005;16(1):5. doi: 10.1097/00001756-200501190-00002
  • Suzuki M, Beuckmann CT, Shikata K, et al. Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Res. 2005;1044(1):116–121. doi: 10.1016/j.brainres.2005.03.002
  • Johnson PL, Molosh A, Fitz SD, et al. Chapter 9 - Orexin, stress, and anxiety/panic states. In: Shekhar A, editor. Progress in brain research [internet]: Elsevier; 2012 cited 2023 May 18. p. 133–161. Available from: https://www.sciencedirect.com/science/article/pii/B9780444594891000094
  • Peres MFP, Vieira DS, Masruha MR, et al. Orexin-A CSF levels correlate with anxiety but not excessive daytime sleepiness in chronic migraine. Headache Medicine. 2011;2:41–45. 2 10.48208/HeadacheMed.2011.9
  • Zhu J-N, Guo C-L, Li H-Z, et al. Dorsomedial hypothalamic nucleus neurons integrate important peripheral feeding-related signals in rats. J Neurosci Res. 2007;85:3193–3204. 14 10.1002/jnr.21420
  • Bigal ME, Lipton RB, Holland PR, et al. Obesity, migraine, and chronic migraine: possible mechanisms of interaction. Neurology. 2007;68(21):1851–1861. doi: 10.1212/01.wnl.0000262045.11646.b1
  • Peterlin BL, Rapoport AM, Kurth T. Migraine and obesity: epidemiology, mechanisms, and implications. Headache. 2010;50(4):631–648. doi: 10.1111/j.1526-4610.2009.01554.x
  • Xue T, Wu X, Chen S, et al. The efficacy and safety of dual orexin receptor antagonists in primary insomnia: a systematic review and network meta-analysis. Sleep Med Rev. 2022;61:101573. doi: 10.1016/j.smrv.2021.101573
  • Weinhold SL, Seeck-Hirschner M, Nowak A, et al. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res. 2014;262:8–13. doi: 10.1016/j.bbr.2013.12.045
  • Charles A. The migraine aura. Continuum. 2018;24(4):1009. doi: 10.1212/CON.0000000000000627
  • Hoffmann J, Supronsinchai W, Akerman S, et al. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis. 2015;74:137–143. doi: 10.1016/j.nbd.2014.10.022
  • Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia. 2015;35(5):379–388. doi: 10.1177/0333102414544979
  • Wimalawansa SJ Circadian variation of plasma calcitonin gene-related peptide in man. J Neuroendocrinology. 1991;3:319–322. 3 10.1111/j.1365-2826.1991.tb00281.x
  • van Oosterhout W, van Someren E, Schoonman G, et al. Chronotypes and circadian timing in migraine. Cephalalgia. 2018;38:617–625. doi: 10.1177/0333102417698953
  • Ong JC, Huang JS, Kuo TF, et al. Characteristics of Insomniacs with self-reported morning and evening chronotypes. J Clin Sleep Med. 2007;3(3):289–294. doi: 10.5664/jcsm.26801
  • Cardinali DP, Brown GM, Pandi-Perumal SR, et al. Chapter 24 - chronotherapy. In: Swaab D, Kreier F Lucassen P, editors. Handbook of clinical neurology [internet]: Elsevier; 2021 cited 2023 Feb 17. p. 357–370. Available from: https://www.sciencedirect.com/science/article/pii/B9780128199756000236
  • Steiner TJ, Stovner LJ, Jensen R, et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21(1):137. doi: 10.1186/s10194-020-01208-0
  • Giffin NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology. 2003;60(6):935–940. doi: 10.1212/01.WNL.0000052998.58526.A9
  • Iio K, Hashimoto K, Nagumo Y, et al. Design and synthesis of orexin 1 receptor-selective agonists. J Med Chem. 2023;66(8):5453–5464. doi: 10.1021/acs.jmedchem.2c01773
  • Ament M, Day K, Stauffer VL, et al. Effect of galcanezumab on severity and symptoms of migraine in phase 3 trials in patients with episodic or chronic migraine. J Headache Pain. 2021;22(1):6. doi: 10.1186/s10194-021-01215-9
  • Dhuria SV, Hanson LR, Frey WH Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci. 2009;98:2501–2515. 7 10.1002/jps.21604