Animals Models for Trigeminal Autonomic Cephalalgias

  • Simon AkermanEmail author
  • Cristina Tassorelli
Part of the Headache book series (HEAD)


Trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders characterised by severe unilateral head pain, coupled with significant lateralised cranial autonomic features. They significantly impair patients’ quality of life, which is also hindered by limited treatment options. Our understanding of these disorders and the development of novel and more effective treatments has been limited by the lack of reliable animal models to explore the pathophysiological mechanisms, and to screen potential therapeutic targets. In this chapter, we will review the current animal models that have been developed to help in our understanding of TACs’ pathophysiology that may be used for the identification and the preclinical evaluation of novel therapeutic leads.


Cluster headache Trigeminovascular Autonomic Parasympathetic Trigeminal autonomic reflex Animal model 


  1. 1.
    Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.CrossRefGoogle Scholar
  2. 2.
    Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalalgia. Lancet Neurol. 2002;1(4):251–7.CrossRefGoogle Scholar
  3. 3.
    Lai T-H, Fuh J-L, Wang S-J. Cranial autonomic symptoms in migraine: characteristics and comparison with cluster headache. J Neurol Neurosurg Psychiatry. 2009;80:1116–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Drummond PD. Autonomic disturbances in cluster headache. Brain. 1988;111(Pt 5):1199–209.PubMedCrossRefGoogle Scholar
  5. 5.
    Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8(8):755–64.CrossRefGoogle Scholar
  6. 6.
    Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107–19. Scholar
  7. 7.
    Finkel AG. Epidemiology of cluster headache. Curr Pain Headache Rep. 2003;7(2):144–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen AS, Matharu MS, Goadsby PJ. Trigeminal autonomic cephalalgias: current and future treatments. Headache. 2007;47(6):969–80.PubMedCrossRefGoogle Scholar
  9. 9.
    May A. Update on the diagnosis and management of trigemino-autonomic headaches. J Neurol. 2006;253(12):1525–32.PubMedCrossRefGoogle Scholar
  10. 10.
    May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005;366(9488):843–55.CrossRefGoogle Scholar
  11. 11.
    Cittadini E, Matharu MS, Goadsby PJ. Paroxysmal hemicrania: a prospective clinical study of 31 cases. Brain. 2008;131(Pt 4):1142–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Cohen AS, Matharu MS, Goadsby PJ. Short-lasting Unilateral neuralgiform Headache Attacks with conjunctival injection and Tearing (SUNCT) or cranial Autonomic features (SUNA). A prospective clinical study of SUNCT and SUNA. Brain. 2006;129:2746–60.CrossRefGoogle Scholar
  13. 13.
    Cittadini E, Goadsby PJ. Hemicrania continua: a clinical study of 39 patients with diagnostic implications. Brain. 2010;133(Pt 7):1973–86.PubMedCrossRefGoogle Scholar
  14. 14.
    May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275–8.CrossRefGoogle Scholar
  15. 15.
    Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol. 2006;59(3):535–45.PubMedCrossRefGoogle Scholar
  16. 16.
    May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol. 1999;46(5):791–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache. 2004;44:747–61.CrossRefGoogle Scholar
  18. 18.
    Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med. 2001;345(19):1428–9.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Walcott BP, Bamber NI, Anderson DE. Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case report. Neurosurgery. 2009;65(5):E997discussion E. Scholar
  20. 20.
    Bartsch T, Falk D, Knudsen K, Reese R, Raethjen J, Mehdorn HM, et al. Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Cephalalgia. 2011;31(13):1405–8. Scholar
  21. 21.
    Leone M, Franzini A, D'Andrea G, Broggi G, Casucci G, Bussone G. Deep brain stimulation to relieve drug-resistant SUNCT. Ann Neurol. 2005;57(6):924–7. Scholar
  22. 22.
    May A, Kaube H, Buchel C, Eichten C, Rijntjes M, Juptner M, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain. 1998;74(1):61–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117(Pt 3):427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicrania—evidence for trigemino-parasympathetic activation. Cephalalgia. 1996;16(6):448–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Tuka B, Szabo N, Toth E, Kincses ZT, Pardutz A, Szok D, et al. Release of PACAP-38 in episodic cluster headache patients - an exploratory study. J Headache Pain. 2016;17(1):69. Scholar
  26. 26.
    Penfield W, McNaughton F. Dural headache and innervation of the dura mater. Arch Neurol Psychiatr. 1940;44:43–75.CrossRefGoogle Scholar
  27. 27.
    Ray BS, Wolff HG. Experimental studies on headache. Pain sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813–56.CrossRefGoogle Scholar
  28. 28.
    Goadsby PJ, Zagami AS. Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain. 1991;114(Pt 2):1001–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Hoskin KL, Zagami AS, Goadsby PJ. Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat. 1999;194(Pt4):579–88.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8(2):89–99.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257–70.PubMedCrossRefGoogle Scholar
  32. 32.
    Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Knight YE, Classey JD, Lasalandra MP, Akerman S, Kowacs F, Hoskin KL, et al. Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat. Brain Res. 2005;1045(1–2):1–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Robert C, Bourgeais L, Arreto CD, Condes-Lara M, Noseda R, Jay T, et al. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. J Neurosci. 2013;33(20):8827–40.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Spencer SE, Sawyer WB, Wada H, Platt KB, Loewy AD. CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study. Brain Res. 1990;534(1–2):149–69.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Hosoya Y, Matsushita M, Sugiura Y. A direct hypothalamic projection to the superior salivatory nucleus neurons in the rat. A study using anterograde autoradiographic and retrograde HRP methods. Brain Res. 1983;266(2):329–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Hosoya Y, Sugiura Y, Ito R, Kohno K. Descending projections from the hypothalamic paraventricular nucleus to the A5 area, including the superior salivatory nucleus, in the rat. Exp Brain Res. 1990;82(3):513–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Akerman S, Williamson DJ, Kaube H, Goadsby PJ. Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol. 2002;137(1):62–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol. 1998;79(2):964–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Benjamin L, Levy MJ, Lasalandra MP, Knight YE, Akerman S, Classey JD, et al. Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis. 2004;16(3):500–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Malick A, Jakubowski M, Elmquist JK, Saper CB, Burstein R. A neurohistochemical blueprint for pain-induced loss of appetite. Proc Natl Acad Sci U S A. 2001;98(17):9930–5.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hoskin KL, Bulmer DCE, Lasalandra M, Jonkman A, Goadsby PJ. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. J Anat. 2001;198:29–35.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides. 1990;16(2):69–75.PubMedCrossRefGoogle Scholar
  44. 44.
    Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol. 2014;1(12):1036–40. Scholar
  45. 45.
    Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache. 2009;49(8):1131–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Akerman S, Romero-Reyes M. Targeting the central projection of the dural trigeminovascular system for migraine prophylaxis. J Cereb Blood Flow Metab. 2017.:271678X17729280; Scholar
  47. 47.
    Burstein R, Jakubowski M. Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol. 2004;55(1):27–36.PubMedCrossRefGoogle Scholar
  48. 48.
    Goadsby PJ, Knight YE. Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5-hydroxy-tryptamine (5-HT(1B/1D)) receptors. Br J Pharmacol. 1997;122(5):918–22.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hoskin KL, Kaube H, Goadsby PJ. Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain. 1996;119(Pt 5):1419–28.PubMedCrossRefGoogle Scholar
  50. 50.
    Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain. 2012;135(Pt 12):3664–75.PubMedCrossRefGoogle Scholar
  51. 51.
    Jakubowski M, Levy D, Kainz V, Zhang XC, Kosaras B, Burstein R. Sensitization of central trigeminovascular neurons: blockade by intravenous naproxen infusion. Neuroscience. 2007;148(2):573–83.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Akerman S, Goadsby PJ. Topiramate inhibits trigeminovascular activation: an intravital microscopy study. Br J Pharmacol. 2005;146(1):7–14.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Storer RJ, Goadsby PJ. Topiramate inhibits trigeminovascular neurons in the cat. Cephalalgia. 2004;24(12):1049–56.PubMedCrossRefGoogle Scholar
  54. 54.
    Ekbom K. Nitroglycerin as a provocative agent in cluster headache. Arch Neurol. 1968;19(5):487–93.CrossRefGoogle Scholar
  55. 55.
    Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain. 1995;60(2):119–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Sances G, Tassorelli C, Pucci E, Ghiotto N, Sandrini G, Nappi G. Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia. 2004;24(2):110–9. Scholar
  57. 57.
    May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55(9):1328–35.CrossRefGoogle Scholar
  58. 58.
    Akerman S, Williamson DJ, Kaube H, Goadsby PJ. The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels. Eur J Pharmacol. 2002;452(2):223–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Koulchitsky S, Fischer MJ, Messlinger K. Calcitonin gene-related peptide receptor inhibition reduces neuronal activity induced by prolonged increase in nitric oxide in the rat spinal trigeminal nucleus. Cephalalgia. 2009;29(4):408–17.PubMedCrossRefGoogle Scholar
  60. 60.
    Lambert GA, Donaldson C, Boers PM, Zagami AS. Activation of trigeminovascular neurons by glyceryl trinitrate. Brain Res. 2000;887(1):203–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brain-stem and forebrain structures of the rat. Brain Res. 1995;682(1–2):167–81.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang X, Kainz V, Zhao J, Strassman AM, Levy D. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol. 2013;73(6):741–50. Scholar
  63. 63.
    Dieterle A, Fischer MJ, Link AS, Neuhuber WL, Messlinger K. Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor. Cephalalgia. 2011;31(1):31–42.PubMedCrossRefGoogle Scholar
  64. 64.
    Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J. Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci. 2002;15(11):1803–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Summ O, Andreou AP, Akerman S, Goadsby PJ. A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches. J Headache Pain. 2010;11(6):477–83. Scholar
  66. 66.
    Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2004;309:56–63.PubMedCrossRefGoogle Scholar
  67. 67.
    Iversen HK, Olesen J, Tfelt-hansen P. Intravenous nitroglycerin as an experimental-model of vascular headache—basic characteristics. Pain. 1989;38(1):17–24.PubMedCrossRefGoogle Scholar
  68. 68.
    Ashina M, Bendtsen L, Jensen R, Olesen J. Nitric oxide-induced headache in patients with chronic tension-type headache. Brain. 2000;123(Pt 9):1830–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Gottselig R, Messlinger K. Noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino-parasympathetic reflex—an experimental model for vascular dysfunctions in cluster headache. Cephalalgia. 2004;24(3):206–14.PubMedCrossRefGoogle Scholar
  70. 70.
    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(3):367–78.CrossRefGoogle Scholar
  71. 71.
    Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779–94. Scholar
  72. 72.
    Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: relevance to migraine. Sci Transl Med. 2015;7(308):308ra157. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Neural and Pain SciencesUniversity of Maryland BaltimoreBaltimoreUSA
  2. 2.Headache Science CentreIRCCS. C. Mondino FoundationPaviaItaly
  3. 3.Department of Brain and Behavioural SciencesUniversity of PaviaPaviaItaly

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