Skip to main content

Advertisement

SpringerLink
Log in

Cluster headache, hypothalamus, and orexin

  • Published:
Current Pain and Headache Reports Aims and scope Submit manuscript

Abstract

Cluster headache (CH) is a highly disabling condition resulting in severe, recurrent unilateral bouts of pain and accompanying autonomic symptoms. This review describes some current views regarding the underlying pathophysiology covering the pain and cranial autonomic (parasympathetic) activation, and highlights the potential importance of the hypothalamus in CH. The hypothalamus is known to modulate many functions and has been shown to be involved in the pathophysiology of a variety of primary headaches, including CH. Hypothalamic structures are likely to underlie the circadian and circannual periodicity of attacks and contribute to the pain and autonomic disturbances. We discuss the hypothalamic involvement in CH and modulation of trigeminovascular processing and examine the emerging involvement of the hypothalamic orexinergic system as a possible key pathway in CH pathophysiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Headache Classification Committee of the International Headache Society: The International Classification of Headache Disorders 2nd ed. Cephalalgia 2004, 24(Suppl 1):1–160.

    Google Scholar 

  2. Drummond PD: Mechanisms of autonomic disturbance in the face during and between attacks of cluster headache. Cephalalgia 2006, 26:633–641.

    Article  PubMed  CAS  Google Scholar 

  3. Holland P, Goadsby PJ: The hypothalamic orexinergic system: pain and primary headaches. Headache 2007, 47:951–962.

    Article  PubMed  Google Scholar 

  4. Obermann M, Yoon MS, Dommes P, et al.: Prevalence of trigeminal autonomic symptoms in migraine: a population-based study. Cephalalgia 2007, 27:504–509.

    Article  PubMed  CAS  Google Scholar 

  5. Frese A, Evers S, May A: Autonomic activation in experimental trigeminal pain. Cephalalgia 2003, 23:67–68.

    Article  PubMed  CAS  Google Scholar 

  6. Hastings MH, Reddy AB, Maywood ES: A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 2003, 4:649–661.

    Article  PubMed  CAS  Google Scholar 

  7. Moore RY: Organization and function of a central nervous system circadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc 1983, 42:2783–2789.

    PubMed  CAS  Google Scholar 

  8. Buijs RM, Wortel J, Van Heerikhuize JJ, et al.: Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 1999, 11:1535–1544.

    Article  PubMed  CAS  Google Scholar 

  9. Abrahamson EE, Leak RK, Moore RY: The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 2001, 12:435–440.

    Article  PubMed  CAS  Google Scholar 

  10. Saper CB: Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian rhythms. Prog Brain Res 2006, 153:243–252.

    Article  PubMed  CAS  Google Scholar 

  11. Bartsch T, Levy MJ, Knight YE, Goadsby PJ: Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004, 109:367–378.

    Article  PubMed  CAS  Google Scholar 

  12. 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, 315:1380–1385.

    Article  PubMed  CAS  Google Scholar 

  13. Holland PR, Akerman S, Goadsby PJ: Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur J Neurosci 2006, 24:2825–2833.

    Article  PubMed  CAS  Google Scholar 

  14. Jiang M, Behbehani MM: 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 2001, 94:139–147.

    Article  PubMed  CAS  Google Scholar 

  15. Lumb BM: Hypothalamic influences on viscero-somatic neurones in the lower thoracic spinal cord of the anaesthetized rat. J Physiol 1990, 424:427–444.

    PubMed  CAS  Google Scholar 

  16. Carstens E: Hypothalamic inhibition of rat dorsal horn neuronal responses to noxious skin heating. Pain 1986, 25:95–107.

    Article  PubMed  CAS  Google Scholar 

  17. Miranda-Cardenas Y, Rojas-Piloni G, Martinez-Lorenzana G, et al.: Oxytocin and electrical stimulation of the paraventricular hypothalamic nucleus produce antinociceptive effects that are reversed by an oxytocin antagonist. Pain 2006, 122:182–189.

    Article  PubMed  CAS  Google Scholar 

  18. Goadsby PJ: Trigeminal autonomic cephalalgias. Pathophysiology and classification. Rev Neurol (Paris) 2005, 161:692–695.

    CAS  Google Scholar 

  19. Pringsheim T: Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 2002, 29:33–40.

    PubMed  Google Scholar 

  20. May A, Bahra A, Buchel C, et al.: PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000, 55:1328–1335.

    PubMed  CAS  Google Scholar 

  21. May A, Bahra A, Buchel C, et al.: Hypothalamic activation in cluster headache attacks. Lancet 1998, 352:275–278.

    Article  PubMed  CAS  Google Scholar 

  22. Leone M, Franzini A, Broggi G, Bussone G: Hypothalamic deep brain stimulation for intractable chronic cluster headache: a 3-year follow-up. Neurol Sci 2003, 24(Suppl 2):S143–S145.

    PubMed  Google Scholar 

  23. Malick A, Jakubowski M, Elmquist JK, et al.: A neuro-histochemical blueprint for pain-induced loss of appetite. Proceedings of the National Academy of Sciences of the United States of America 2001, 98:14186.

    Article  CAS  Google Scholar 

  24. Benjamin L, Levy MJ, Lasalandra MP, et al.: Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis 2004, 16:500–505.

    Article  PubMed  CAS  Google Scholar 

  25. Ferguson AV, Samson WK: The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 2003, 24:141–150.

    Article  PubMed  CAS  Google Scholar 

  26. Siegel JM: Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol 2004, 55:125–148.

    Article  PubMed  Google Scholar 

  27. Sakurai T: Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 2005, 9:231–241.

    Article  PubMed  Google Scholar 

  28. Bingham S, Davey PT, Babbs AJ, et al.: Orexin-A, an hypothalamic peptide with analgesic properties. Pain 2001, 92:81–90.

    Article  PubMed  CAS  Google Scholar 

  29. 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, 1044:76–86.

    Article  PubMed  CAS  Google Scholar 

  30. Peyron C, Tighe DK, van den Pol AN, et al.: Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998, 18:9996–10015.

    PubMed  CAS  Google Scholar 

  31. Trivedi P, Yu H, MacNeil DJ, et al.: Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998, 438:71–75.

    Article  PubMed  CAS  Google Scholar 

  32. 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, 137:170–176.

    Article  PubMed  CAS  Google Scholar 

  33. 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, 6:991–997.

    Article  PubMed  CAS  Google Scholar 

  34. Dahmen N, Kasten M, Wieczorek S, et al.: Increased frequency of migraine in narcoleptic patients: a confirmatory study. Cephalalgia 2003, 23:14–19.

    Article  PubMed  CAS  Google Scholar 

  35. Dexter JD, Weitzman ED: The relationship of nocturnal headaches to sleep stage patterns. Neurology 1970, 20:513–518.

    PubMed  CAS  Google Scholar 

  36. Rainero I, Gallone S, Rubino E, et al.: Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache. Headache 2008, 48:1108–1114.

    Article  PubMed  Google Scholar 

  37. 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, 66:1888–1893.

    Article  PubMed  CAS  Google Scholar 

  38. Schurks 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, 27:363–367.

    Article  PubMed  CAS  Google Scholar 

  39. Sprenger T, Boecker H, Tolle TR, et al.: Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004, 62:516–517.

    PubMed  CAS  Google Scholar 

  40. Denuelle M, Fabre N, Payoux P, et al.: Brainstem and hypothalamic activation in spontaneous migraine attacks. Cephalalgia 2004, 24:775–814.

    Article  Google Scholar 

  41. Johren O, Neidert SJ, Kummer M, Dominiak P: Sexually dimorphic expression of prepro-orexin mRNA in the rat hypothalamus. Peptides 2002, 23:1177–1180.

    Article  PubMed  CAS  Google Scholar 

  42. Holland PR, Akerman S, Lasalandra M, et al.: Hypothalamic neurons that contain orexin A and B express c-fos in response to superior sagittal sinus (SSS) stimulation in the cat. Cephalalgia 2005, 25:1194–1195.

    Article  Google Scholar 

  43. Holland PR, Akerman S, Goadsby PJ: Hypothalamic neuropeptides orexin A and B modulation of central and peripheral pathways in the pathophysiology of migraine. Cephalalgia 2005, 25:857.

    Google Scholar 

  44. Holland PR, Akerman S, Lasalandra MP, Goadsby PJ: Orexin A antinociceptive effects in the ventrolateral periaqueductal gray are blocked by 5HT 1(B/D) receptor antagonism. Ann Neurol 2008, 64:S26.

    Google Scholar 

  45. Smart D: Orexins: a new family of neuropeptides. Br J Anaesth 1999, 83:695–697.

    PubMed  CAS  Google Scholar 

  46. Brisbare-Roch C, Dingemanse J, Koberstein R, et al.: Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007, 13:150–155.

    Article  PubMed  CAS  Google Scholar 

  47. van den Pol AN: Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 1999, 19:3171–3182.

    PubMed  Google Scholar 

  48. Yamamoto T, Saito O, Shono K, Hirasawa S: Activation of spinal orexin-1 receptor produces anti-allodynic effect in the rat carrageenan test. Eur J Pharmacol 2003, 481:175–180.

    Article  PubMed  CAS  Google Scholar 

  49. Liu RJ, van den Pol AN, Aghajanian GK: Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002, 22:9453–9464.

    PubMed  CAS  Google Scholar 

  50. Kohlmeier KA, Inoue T, Leonard CS: Hypocretin/Orexin peptide signalling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol 2004, 92:221–235.

    Article  PubMed  CAS  Google Scholar 

  51. van den Pol AN, Gao XB, Obrietan K, et al.: Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 1998, 18:7962–7971.

    PubMed  Google Scholar 

  52. Eriksson KS, Sergeeva OA, Selbach O, Haas HL: Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons. Eur J Neurosci 2004, 19:1278–1284.

    Article  PubMed  Google Scholar 

  53. Matharu MS, Levy MJ, Meeran K, Goadsby PJ: Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol 2004, 56:488–494.

    Article  PubMed  CAS  Google Scholar 

  54. Kapicioglu S, Gokce E, Kapicioglu Z, Ovali E: Treatment of migraine attacks with a long-acting somatostatin analogue (octreotide, SMS 201–995). Cephalalgia 1997, 17:27–30.

    Article  PubMed  CAS  Google Scholar 

  55. Levy MJ, Matharu MS, Bhola R, et al.: Octreotide is not effective in the acute treatment of migraine. Cephalalgia 2005, 25:48–55.

    Article  PubMed  CAS  Google Scholar 

  56. Chapman V, Dickenson AH: The effects of sandostatin and somatostatin on nociceptive transmission in the dorsal horn of the rat spinal cord. Neuropeptides 1992, 23:147–152.

    Article  PubMed  CAS  Google Scholar 

  57. Tashev R, Belcheva S, Milenov K, Belcheva I: Antinociceptive effect of somatostatin microinjected into caudate putamen. Peptides 2001, 22:1079–1083.

    Article  PubMed  CAS  Google Scholar 

  58. Helmchen C, Fu QG, Sandkuhler J: Inhibition of spinal nociceptive neurons by microinjections of somatostatin into the nucleus raphe magnus and the midbrain periaqueductal gray of the anesthetized cat. Neurosci Lett 1995, 187:137–141.

    Article  PubMed  CAS  Google Scholar 

  59. Bereiter DA: Morphine and somatostatin analogue reduce c-fos expression in trigeminal subnucleus caudalis produced by corneal stimulation in the rat. Neuroscience 1997, 77:863–874.

    Article  PubMed  CAS  Google Scholar 

  60. Bartsch T, Levy MJ, Knight YE, Goadsby PJ: Inhibition of nociceptive dural input in the trigeminal nucleus caudalis by somatostatin receptor blockade in the posterior hypothalamus. Pain 2005, 117:30–39.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Headache Research Group, Department of Neurology, University of California, San Francisco, Box 0114, 505 Parnassus Avenue, San Francisco, CA, 94143, USA

    Philip R. Holland

Authors
  1. Philip R. Holland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Goadsby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip R. Holland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holland, P.R., Goadsby, P.J. Cluster headache, hypothalamus, and orexin. Current Science Inc 13, 147–154 (2009). https://doi.org/10.1007/s11916-009-0025-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-009-0025-x

Keywords

Search

Navigation