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Chronic Headache pp 289–308Cite as

Animal Models in Chronic Daily Headache (CDH) and Pathophysiology of CDH

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Abstract

Chronic migraine (CM) has complex pathophysiology that cannot be easily studied in humans. Therefore, animal models are ideally suited for this type of investigation and have played crucial roles in our understanding of CM pathophysiology and aid in treatment. Multidisciplinary approaches used in animal models explore anatomical circuits, phenotypic traits, electrophysiological activities, biochemical pathways, and genetic manipulations. Examination of pathophysiology, therapeutic and prophylactic treatment options, drug effects, and non-pharmacological therapies is explored in preclinical settings and helps improve their applications in clinical practice. On the other hand, known CM therapies also benefit from animal models when unraveling drug mechanisms, sensitivity, and toxicity. Thus, even with known limitations, animal models are unraveling CM mechanisms and contributing to the development of therapeutic tools with translational implications that will guide personalized therapies.

Among all chronic daily headache (CDH) disorders, chronic migraine (CM) and chronic tension-type headache (CTTH) contribute to most cases of CDH, followed by new daily persistent headache (NDPH), medication oversue headache (MOH), and hemicrania continua. The most studied CDH type in animal models is CM. We will focus on animal models of CM in this chapter.

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Abbreviations

5,7-DHT:

 5,7-Dihydroxytryptamine creatinine sulfate

BAEP:

  Brainstem auditory-evoked potential

BBB:

   Blood-brain barrier

BoNT-A:

 Botulinum neurotoxin type A

CBF:

      Cerebral blood flow

CDH:

   Chronic daily headache

CGRP:

  Calcitonin gene-related peptide

CM:

   Chronic migraine

CSD:

    Cortical spreading depression

CTTH:

   Chronic tension-type headache

EPs:

   Evoked potentials

FHM:

   Familial hemiplegic migraine

fMRI:

   Functional magnetic resonance imaging

IM:

    Inflammatory mediator

IP:

    Intraperitoneal

IS:

    Inflammatory soup

MOH:

   Medication overuse headache

NDPH:

   New daily persistent headache

NO:

    Nitric oxide

NTG:

   Nitroglycerin

nVNS:

  Noninvasive vagus nerve stimulation

ONS:

   Occipital nerve stimulation

PAG:

    Periaqueductal gray

RVM:

   Rostral ventromedial medulla

SD:

    Sprague-Dawley

TCC:

    Trigeminocervical complex

tDCS:

   Transcranial direct current stimulation

TENS:

   Transcutaneous electrical nerve stimulation

TMS:

    Transcranial magnetic stimulation

TNC:

    Trigeminal nucleus caudalis

VPM:

   Ventral posteromedial nucleus (of the thalamus)

References

  1. Bigal ME, Lipton RB. What predicts the change from episodic to chronic migraine? Curr Opin Neurol. 2009;22(3):269–76.

    Article  PubMed  Google Scholar 

  2. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;71(8):559–66.

    Article  PubMed  Google Scholar 

  3. McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol. 2014;87(1):162–71.

    Article  PubMed  CAS  Google Scholar 

  4. McGonigle P. Animal models of CNS disorders. Biochem Pharmacol. 2014;87(1):140–9.

    Article  PubMed  CAS  Google Scholar 

  5. Storer RJ, Supronsinchai W, Srikiatkhachorn A. Animal models of chronic migraine. Curr Pain Headache Rep. 2015;19(1):467.

    Article  PubMed  Google Scholar 

  6. Walling I, Smith H, Gee LE, Kaszuba B, Chockalingam A, Barborica A, et al. Occipital nerve stimulation attenuates neuronal firing response to mechanical stimuli in the ventral posteromedial thalamus of a rodent model of chronic migraine. Neurosurgery. 2017.

    Google Scholar 

  7. De La Cruz P, Gee L, Walling I, Morris B, Chen N, Kumar V, et al. Treatment of allodynia by occipital nerve stimulation in chronic migraine rodent. Neurosurgery. 2015;77(3):479–85. discussion 85.

    Article  Google Scholar 

  8. Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves R, et al. Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol. 2010;68(1):81–91.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boyer N, Dallel R, Artola A, Monconduit L. General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain. 2014;155(7):1196–205.

    Article  PubMed  Google Scholar 

  10. Oshinsky ML, Gomonchareonsiri S. Episodic dural stimulation in awake rats: a model for recurrent headache. Headache. 2007;47(7):1026–36.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Burstein R, Zhang X, Levy D, Aoki KR, Brin MF. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia. 2014;34(11):853–69.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A. Characterization of a novel model of chronic migraine. Pain. 2014;155(2):269–74.

    Article  PubMed  CAS  Google Scholar 

  13. Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA. The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia. 2016;36(11):1048–56.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dallel R, Descheemaeker A, Luccarini P. Recurrent administration of the nitric oxide donor, isosorbide dinitrate, induces a persistent cephalic cutaneous hypersensitivity: a model for migraine progression. Cephalalgia. 2017;333102417714032.

    Google Scholar 

  15. Cui Y, Li QH, Yamada H, Watanabe Y, Kataoka Y. Chronic degeneration of dorsal raphe serotonergic neurons modulates cortical spreading depression: a possible pathophysiology of migraine. J Neurosci Res. 2013;91(6):737–44.

    Article  PubMed  CAS  Google Scholar 

  16. Kitamura E, Kanazawa N, Hamada J. Hyperleptinemia increases the susceptibility of the cortex to generate cortical spreading depression. Cephalalgia. 2015;35(4):327–34.

    Article  PubMed  Google Scholar 

  17. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron. 2004;41(5):701–10.

    Article  PubMed  Google Scholar 

  18. Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, Pizzorusso T, et al. Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet. 2011;7(6):e1002129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Ikeda K, Onaka T, Yamakado M, Nakai J, Ishikawa TO, Taketo MM, et al. Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice. J Neurosci. 2003;23(11):4667–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, et al. Casein kinase i delta mutations in familial migraine and advanced sleep phase. Sci Transl Med. 2013;5(183):183ra56. 1–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Eikermann-Haerter K, Yuzawa I, Dilekoz E, Joutel A, Moskowitz MA, Ayata C. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression. Ann Neurol. 2011;69(2):413–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chen SP, Qin T, Seidel JL, Zheng Y, Eikermann M, Ferrari MD, et al. Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation. Brain. 2017;140(6):1643–56.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Marquez de Prado B, Hammond DL, Russo AF. Genetic enhancement of calcitonin gene-related Peptide-induced central sensitization to mechanical stimuli in mice. J Pain. 2009;10(9):992–1000.

    Article  PubMed  CAS  Google Scholar 

  24. Fu H, Fang P, Zhou HY, Zhou J, Yu XW, Ni M, et al. Acid-sensing ion channels in trigeminal ganglion neurons innervating the orofacial region contribute to orofacial inflammatory pain. Clin Exp Pharmacol Physiol. 2016;43(2):193–202.

    Article  PubMed  CAS  Google Scholar 

  25. Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet. 2010;42(10):869–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, Launer LJ, et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet. 2011;43(7):695–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, et al. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012;44(7):777–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kayama Y, Shibata M, Takizawa T, Ibata K, Shimizu T, Ebine T, et al. Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: relevance to migraine pathophysiology. Cephalalgia. 2017;333102417712719.

    Google Scholar 

  29. Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. In: Pain; 2017.

    Google Scholar 

  30. Oshinsky ML, Sanghvi MM, Maxwell CR, Gonzalez D, Spangenberg RJ, Cooper M, et al. Spontaneous trigeminal allodynia in rats: a model of primary headache. Headache. 2012;52(9):1336–49.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365–91.

    Article  PubMed  CAS  Google Scholar 

  32. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8(2):89–99.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Levy D. Migraine pain and nociceptor activation—where do we stand? Headache. 2010;50(5):909–16.

    Article  PubMed  Google Scholar 

  34. Levy D. Migraine pain, meningeal inflammation, and mast cells. Curr Pain Headache Rep. 2009;13(3):237–40.

    Article  PubMed  Google Scholar 

  35. Waeber C, Moskowitz MA. Migraine as an inflammatory disorder. Neurology. 2005;64(10 Suppl 2):S9–15.

    Article  PubMed  Google Scholar 

  36. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013.

    Google Scholar 

  37. Schulte LH, Allers A, May A. Hypothalamus as a mediator of chronic migraine: evidence from high-resolution fMRI. Neurology. 2017;88(21):2011–6.

    Article  PubMed  Google Scholar 

  38. Capuano A, De Corato A, Lisi L, Tringali G, Navarra P, Dello Russo C. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol Pain. 2009;5:43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Galeotti N, Ghelardini C. St. John's wort reversal of meningeal nociception: a natural therapeutic perspective for migraine pain. Phytomedicine. 2013;20(10):930–8.

    Article  PubMed  CAS  Google Scholar 

  40. Ashina M, Simonsen H, Bendtsen L, Jensen R, Olesen J. Glyceryl trinitrate may trigger endogenous nitric oxide production in patients with chronic tension-type headache. Cephalalgia. 2004;24(11):967–72.

    Article  PubMed  CAS  Google Scholar 

  41. Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther. 2008;120(2):157–71.

    Article  PubMed  CAS  Google Scholar 

  42. Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain. 1989;38(1):17–24.

    Article  PubMed  CAS  Google Scholar 

  43. Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain. 2004;110(3):675–80.

    Article  PubMed  CAS  Google Scholar 

  44. Torfgard K, Ahlner J, Axelsson KL, Norlander B, Bertler A. Tissue levels of glyceryl trinitrate and cGMP after in vivo administration in rat, and the effect of tolerance development. Can J Physiol Pharmacol. 1991;69(9):1257–61.

    Article  PubMed  CAS  Google Scholar 

  45. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43(2):109–42.

    PubMed  CAS  Google Scholar 

  46. Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric oxide synthase inhibition in migraine. Lancet. 1997;349(9049):401–2.

    Article  PubMed  CAS  Google Scholar 

  47. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 1995;682(1–2):167–81.

    Article  PubMed  CAS  Google Scholar 

  48. Bergerot A, Holland PR, Akerman S, Bartsch T, Ahn AH, MaassenVanDenBrink A, et al. Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci. 2006;24(6):1517–34.

    Article  PubMed  CAS  Google Scholar 

  49. Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI, et al. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia. 2010;30(2):170–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Capuano A, Greco MC, Navarra P, Tringali G. Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization. Eur J Pharmacol. 2014;740:97–102.

    Article  PubMed  CAS  Google Scholar 

  51. Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, et al. Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis. 2012;45(1):633–44.

    Article  PubMed  CAS  Google Scholar 

  52. Farkas S, Bolcskei K, Markovics A, Varga A, Kis-Varga A, Kormos V, et al. Utility of different outcome measures for the nitroglycerin model of migraine in mice. J Pharmacol Toxicol Methods. 2016;77:33–44.

    Article  PubMed  CAS  Google Scholar 

  53. Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in the United States: a life-span study. Cephalalgia. 2010;30(9):1065–72.

    Article  PubMed  CAS  Google Scholar 

  54. Greco R, Tassorelli C, Mangione AS, Smeraldi A, Allena M, Sandrini G, et al. Effect of sex and estrogens on neuronal activation in an animal model of migraine. Headache. 2013;53(2):288–96.

    Article  PubMed  Google Scholar 

  55. Greco R, Tassorelli C, Armentero MT, Sandrini G, Nappi G, Blandini F. Role of central dopaminergic circuitry in pain processing and nitroglycerin-induced hyperalgesia. Brain Res. 2008;1238:215–23.

    Article  PubMed  CAS  Google Scholar 

  56. Harrington MG, Chekmenev EY, Schepkin V, Fonteh AN, Arakaki X. Sodium MRI in a rat migraine model and a NEURON simulation study support a role for sodium in migraine. Cephalalgia. 2011;31(12):1254–65.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bree D, Levy D. Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: implications for mechanisms of post-traumatic headache. Cephalalgia. 2016.

    Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. Levy D, Strassman AM. Mechanical response properties of A and C primary afferent neurons innervating the rat intracranial dura. J Neurophysiol. 2002;88(6):3021–31.

    Article  PubMed  Google Scholar 

  60. Boyer N, Signoret-Genest J, Artola A, Dallel R, Monconduit L. Propranolol treatment prevents chronic central sensitization induced by repeated dural stimulation. Pain. 2017.

    Google Scholar 

  61. Fried NT, Maxwell CR, Elliott MB, Oshinsky ML. Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia. Cephalalgia. 2017;333102417703764.

    Google Scholar 

  62. Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9(11):637–44.

    Article  PubMed  Google Scholar 

  63. Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci. 2010;30(26):8807–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69(5):855–65.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A. Serotonin depletion, cortical spreading depression, and trigeminal nociception. Headache. 2006;46(1):34–9.

    Article  PubMed  Google Scholar 

  66. Oury F, Karsenty G. Towards a serotonin-dependent leptin roadmap in the brain. Trends Endocrinol Metab. 2011;22(9):382–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Kitamura E, Hamada J, Kanazawa N, Yonekura J, Masuda R, Sakai F, et al. The effect of orexin-A on the pathological mechanism in the rat focal cerebral ischemia. Neurosci Res. 2010;68(2):154–7.

    Article  PubMed  CAS  Google Scholar 

  68. Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002;967:379–88.

    Article  PubMed  CAS  Google Scholar 

  69. Berger M, Speckmann EJ, Pape HC, Gorji A. Spreading depression enhances human neocortical excitability in vitro. Cephalalgia. 2008;28(5):558–62.

    Article  PubMed  CAS  Google Scholar 

  70. Vezzani A, Friedman A. Brain inflammation as a biomarker in epilepsy. Biomark Med. 2011;5(5):607–14.

    Article  PubMed  CAS  Google Scholar 

  71. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–9.

    Article  PubMed  CAS  Google Scholar 

  72. Bigal ME, Ashina S, Burstein R, Reed ML, Buse D, Serrano D, et al. Prevalence and characteristics of allodynia in headache sufferers: a population study. Neurology. 2008;70(17):1525–33.

    Article  PubMed  CAS  Google Scholar 

  73. Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Ann Neurol. 2008;63(2):148–58.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Ashkenazi A, Silberstein S, Jakubowski M, Burstein R. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia. 2007;27(4):325–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47(5):614–24.

    Article  PubMed  CAS  Google Scholar 

  76. Lovati C, D'Amico D, Bertora P, Rosa S, Suardelli M, Mailland E, et al. Acute and interictal allodynia in patients with different headache forms: an Italian pilot study. Headache. 2008;48(2):272–7.

    Article  PubMed  Google Scholar 

  77. Louter MA, Bosker JE, van Oosterhout WP, van Zwet EW, Zitman FG, Ferrari MD, et al. Cutaneous allodynia as a predictor of migraine chronification. Brain. 2013;136(Pt 11):3489–96.

    Article  PubMed  Google Scholar 

  78. Mathew PG, Cutrer FM, Garza I. A touchy subject: an assessment of cutaneous allodynia in a chronic migraine population. J Pain Res. 2016;9:101–4.

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioravanti B, De Felice M, et al. Medullary pain facilitating neurons mediate allodynia in headache-related pain. Ann Neurol. 2009;65(2):184–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. 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.

    Article  PubMed  CAS  Google Scholar 

  82. Dalsgaard-Nielsen T. Migraine diagnostics with special reference to pharmacological tests. Int Arch Allergy Appl Immunol. 1955;7(4–6):312–22.

    Article  PubMed  CAS  Google Scholar 

  83. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport. 1993;4(8):1027–30.

    Article  PubMed  CAS  Google Scholar 

  84. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793–803.

    Article  PubMed  CAS  Google Scholar 

  85. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804–14.

    Article  PubMed  CAS  Google Scholar 

  86. Zhang X, Strassman AM, Novack V, Brin MF, Burstein R. Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia. 2016;36(9):875–86.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Naumann M, Carruthers A, Carruthers J, Aurora SK, Zafonte R, Abu-Shakra S, et al. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX(R)) across multiple indications. Mov Disord. 2010;25(13):2211–8.

    Article  PubMed  Google Scholar 

  88. Kalita J, Bhoi SK, Misra UK. Is lack of habituation of evoked potential a biological marker of migraine? Clin J Pain. 2014;30(8):724–9.

    Article  PubMed  Google Scholar 

  89. Arakaki X, Galbraith G, Pikov V, Fonteh AN, Harrington MG. Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine. Brain Res. 2014;1563:110–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Sand T, Zhitniy N, White LR, Stovner LJ. Brainstem auditory-evoked potential habituation and intensity-dependence related to serotonin metabolism in migraine: a longitudinal study. Clin Neurophysiol. 2008;119(5):1190–200.

    Article  PubMed  Google Scholar 

  91. Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644–55.

    Article  PubMed  Google Scholar 

  92. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004;55(1):19–26.

    Article  PubMed  CAS  Google Scholar 

  93. Perini F, De Boni A. Peripheral neuromodulation in chronic migraine. Neurol Sci. 2012;33(Suppl 1):S29–31.

    Article  PubMed  Google Scholar 

  94. Notaro P, Buratti E, Meroni A, Montagna MC, Rubino FG, Voltolini A. The effects of peripheral occipital nerve stimulation for the treatment of patients suffering from chronic migraine: a single center experience. Pain Physician. 2014;17(3):E369–74.

    PubMed  Google Scholar 

  95. Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database Syst Rev. 2008(3):CD003222.

    Google Scholar 

  96. McQuay HJ, Moore RA, Eccleston C, Morley S, Williams AC. Systematic review of outpatient services for chronic pain control. Health Technol Assess. 1997;1(6):i–iv. 1–135.

    PubMed  CAS  Google Scholar 

  97. Vincent MB, Ekman R, Edvinsson L, Sand T, Sjaastad O. Reduction of calcitonin gene-related peptide in jugular blood following electrical stimulation of rat greater occipital nerve. Cephalalgia. 1992;12(5):275–9.

    Article  PubMed  CAS  Google Scholar 

  98. Didier HA, Di Fiore P, Marchetti C, Tullo V, Frediani F, Arlotti M, et al. Electromyography data in chronic migraine patients by using neurostimulation with the Cefaly(R) device. Neurol Sci. 2015;36(Suppl 1):115–9.

    Article  PubMed  Google Scholar 

  99. Wall PD. The gate control theory of pain mechanisms. A re-examination and re-statement. Brain. 1978;101(1):1–18.

    Article  PubMed  CAS  Google Scholar 

  100. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34(12):986–93.

    Article  PubMed  CAS  Google Scholar 

  101. Chen SP, Ay I, de Morais AL, Qin T, Zheng Y, Sadeghian H, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016;157(4):797–805.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037–42.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Silberstein SD, Calhoun AH, Lipton RB, Grosberg BM, Cady RK, Dorlas S, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529–38.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553–622.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Goadsby PJ. Pathophysiology of migraine. Neurol Clin. 2009;27(2):335–60.

    Article  PubMed  Google Scholar 

  106. Oshinsky ML, Luo J. Neurochemistry of trigeminal activation in an animal model of migraine. Headache. 2006;46(Suppl 1):S39–44.

    Article  PubMed  Google Scholar 

  107. Johnson KW, Phebus LA, Cohen ML. Serotonin in migraine: theories, animal models and emerging therapies. Prog Drug Res. 1998;51:219–44.

    Article  PubMed  CAS  Google Scholar 

  108. Yisarakun W, Chantong C, Supornsilpchai W, Thongtan T, Srikiatkhachorn A, Reuangwechvorachai P, et al. Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model. Neuropeptides. 2015;51:9–16.

    Article  PubMed  CAS  Google Scholar 

  109. Arakaki X, McCleary P, Techy M, Chiang J, Kuo L, Fonteh AN, et al. Na,K-ATPase alpha isoforms at the blood-cerebrospinal fluid-trigeminal nerve and blood-retina interfaces in the rat. Fluids Barriers CNS. 2013;10(1):14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Moye LS, Pradhan AAA. Animal model of chronic migraine-associated pain. Curr Protoc Neurosci. 2017;80:9.60.1–9.

    Article  Google Scholar 

  111. Greco R, Mangione AS, Sandrini G, Maccarrone M, Nappi G, Tassorelli C. Effects of anandamide in migraine: data from an animal model. J Headache Pain. 2011;12(2):177–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Greco R, Bandiera T, Mangione AS, Demartini C, Siani F, Nappi G, et al. Effects of peripheral FAAH blockade on NTG-induced hyperalgesia—evaluation of URB937 in an animal model of migraine. Cephalalgia. 2015;35(12):1065–76.

    Article  PubMed  CAS  Google Scholar 

  113. Bolay H, Berman NE, Akcali D. Sex-related differences in animal models of migraine headache. Headache. 2011;51(6):891–904.

    Article  PubMed  Google Scholar 

  114. Bongsebandhu-phubhakdi S, Srikiatkhachorn A. Pathophysiology of medication-overuse headache: implications from animal studies. Curr Pain Headache Rep. 2012;16(1):110–5.

    Article  PubMed  Google Scholar 

  115. Green AL, Gu P, De Felice M, Dodick D, Ossipov MH, Porreca F. Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia. 2014;34(8):594–604.

    Article  PubMed  Google Scholar 

  116. Wu B, Wang S, Qin G, Xie J, Tan G, Zhou J, et al. Protein kinase C gamma contributes to central sensitization in a rat model of chronic migraine. J Mol Neurosci. 2017.

    Google Scholar 

  117. Dong X, Hu Y, Jing L, Chen J. Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine. Mol Med Rep. 2015;12(2):1803–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Guo JQ, Deng HH, Bo X, Yang XS. Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine. Biol Open. 2017;6(1):8–16.

    Article  PubMed  CAS  Google Scholar 

  119. Liu YY, Jiao ZY, Li W, Tian Q. PI3K/AKT signaling pathway activation in a rat model of migraine. Mol Med Rep. 2017.

    Google Scholar 

  120. Qin G, Xie J, Chen L, Wu B, Gui B, Zhou J. PTEN inhibition preserves trigeminal nucleus caudalis neuron activation through tyrosine phosphorylation of the NR2B subunit at Tyr1472 of the NMDA receptor in a rat model of recurrent migraine. Neurol Res. 2016;38(4):320–6.

    Article  PubMed  CAS  Google Scholar 

  121. Ghosh J, Pradhan S, Mittal B. Multilocus analysis of hormonal, neurotransmitter, inflammatory pathways and genome-wide associated variants in migraine susceptibility. Eur J Neurol. 2014;21(7):1011–20.

    Article  PubMed  CAS  Google Scholar 

  122. Di Guilmi MN, Wang T, Inchauspe CG, Forsythe ID, Ferrari MD, van den Maagdenberg AM, et al. Synaptic gain-of-function effects of mutant Cav2.1 channels in a mouse model of familial hemiplegic migraine are due to increased basal [Ca2+]i. J Neurosci. 2014;34(21):7047–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol. 2015;14(1):65–80.

    Article  PubMed  CAS  Google Scholar 

  124. Bottger P, Glerup S, Gesslein B, Illarionova NB, Isaksen TJ, Heuck A, et al. Glutamate-system defects behind psychiatric manifestations in a familial hemiplegic migraine type 2 disease-mutation mouse model. Sci Rep. 2016;6:22047.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Munro G, Jansen-Olesen I, Olesen J. Animal models of pain and migraine in drug discovery. Drug Discov Today. 2017;22(7):1103–11.

    Article  PubMed  CAS  Google Scholar 

  126. Connor HE, Feniuk W, Beattie DT, North PC, Oxford AW, Saynor DA, et al. Naratriptan: biological profile in animal models relevant to migraine. Cephalalgia. 1997;17(3):145–52.

    Article  PubMed  CAS  Google Scholar 

  127. Humphrey PP, Feniuk W, Marriott AS, Tanner RJ, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol. 1991;31(5):282–90.

    Article  PubMed  CAS  Google Scholar 

  128. Tepper SJ, Stillman MJ. Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine. Headache. 2008;48(8):1259–68.

    Article  PubMed  Google Scholar 

  129. Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine prevention? Curr Treat Options Neurol. 2017;19(8):27.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Karsan N, Goadsby PJ. Calcitonin gene-related peptide and migraine. Curr Opin Neurol. 2015;28(3):250–4.

    Article  PubMed  CAS  Google Scholar 

  131. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821–8.

    Article  PubMed  CAS  Google Scholar 

  132. De Felice M, Ossipov MH, Wang R, Lai J, Chichorro J, Meng I, et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol. 2010;67(3):325–37.

    PubMed  PubMed Central  Google Scholar 

  133. Kopruszinski CM, Xie JY, Eyde NM, Remeniuk B, Walter S, Stratton J, et al. Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents. Cephalalgia. 2017;37(6):560–70.

    Article  PubMed  Google Scholar 

  134. Silberstein SD. Topiramate in migraine prevention: a 2016 perspective. Headache. 2017;57(1):165–78.

    Article  PubMed  Google Scholar 

  135. Chen SP, Tolner EA, Eikermann-Haerter K. Animal models of monogenic migraine. Cephalalgia. 2016;36(7):704–21.

    Article  PubMed  Google Scholar 

  136. Friedrich T, Tavraz NN, Junghans C. ATP1A2 mutations in migraine: seeing through the facets of an ion pump onto the neurobiology of disease. Front Physiol. 2016;7:239.

    PubMed  PubMed Central  Google Scholar 

  137. Isaksen TJ, Lykke-Hartmann K. Insights into the pathology of the alpha2-Na(+)/K(+)-ATPase in neurological disorders; lessons from animal models. Front Physiol. 2016;7:161.

    Article  PubMed  PubMed Central  Google Scholar 

  138. van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE, et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann Neurol. 2010;67(1):85–98.

    Article  PubMed  CAS  Google Scholar 

  139. van Oosterhout F, Michel S, Deboer T, Houben T, van de Ven RC, Albus H, et al. Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice. Ann Neurol. 2008;64(3):315–24.

    Article  PubMed  Google Scholar 

  140. Eising E, Shyti R, t Hoen PAC, Vijfhuizen LS, SMH H, LAM B, et al. Cortical spreading depression causes unique dysregulation of inflammatory pathways in a transgenic mouse model of migraine. Mol Neurobiol. 2017;54(4):2986–96.

    Article  PubMed  CAS  Google Scholar 

  141. Franceschini A, Nair A, Bele T, van den Maagdenberg AM, Nistri A, Fabbretti E. Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine. BMC Neurosci. 2012;13:143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Franceschini A, Vilotti S, Ferrari MD, van den Maagdenberg AM, Nistri A, Fabbretti E. TNFalpha levels and macrophages expression reflect an inflammatory potential of trigeminal ganglia in a mouse model of familial hemiplegic migraine. PLoS One. 2013;8(1):e52394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Gnanasekaran A, Bele T, Hullugundi S, Simonetti M, Ferrari MD, van den Maagdenberg AM, et al. Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. Mol Pain. 2013;9:62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Gnanasekaran A, Sundukova M, van den Maagdenberg AM, Fabbretti E, Nistri A. Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol Pain. 2011;7:77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Nair A, Simonetti M, Birsa N, Ferrari MD, van den Maagdenberg AM, Giniatullin R, et al. Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain. 2010;6:48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Vilotti S, Vana N, Van den Maagdenberg AM, Nistri A. Expression and function of calcitonin gene-related peptide (CGRP) receptors in trigeminal ganglia of R192Q Cacna1a knock-in mice. Neurosci Lett. 2016;620:104–10.

    Article  PubMed  CAS  Google Scholar 

  147. Hullugundi SK, Ferrari MD, van den Maagdenberg AM, Nistri A. The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1). PLoS One. 2013;8(4):e60677.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest. 2009;119(1):99–109.

    PubMed  CAS  Google Scholar 

  149. Moseley AE, Williams MT, Schaefer TL, Bohanan CS, Neumann JC, Behbehani MM, et al. Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. J Neurosci. 2007;27(3):616–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Lingrel JB, Williams MT, Vorhees CV, Moseley AE. Na,K-ATPase and the role of alpha isoforms in behavior. J Bioenerg Biomembr. 2007;39(5–6):385–9.

    Article  PubMed  CAS  Google Scholar 

  151. Burstein R, Jakubowski M. Neural substrate of depression during migraine. Neurol Sci. 2009;30(Suppl 1):S27–31.

    Article  PubMed  Google Scholar 

  152. Desouza DD, Woldeamanue YW, Peretz AM, Sanjanwala BM, Cowan RP, editors. Interactions between affective measures and amygdala volume in chronic migraine: associations in the absence of group volumetric differences. 18th International Headache Congress; 2017 September 7–10. Vancouver: Cephalalgia; 2017.

    Google Scholar 

  153. Michael G. Harrington XA, Alfred N. Fonteh, Natalie Chen, Eduard, Chekmenev VS, Jiarong Chiang. Na,K-ATPase is a regulator of rodent central sensitization: implications for migraine. American Society for Biochemistry and Molecular Biology, 14th International Conference on Na,K-ATPase August 3, 2014 - September 5, 2014; De Werelt Conference Centre, Lunteren, NL2014.

    Google Scholar 

  154. Kalume F, Yu FH, Westenbroek RE, Scheuer T, Catterall WA. Reduced sodium current in Purkinje neurons from Nav1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy. J Neurosci. 2007;27(41):11065–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci. 2007;27(22):5903–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci. 2006;9(9):1142–9.

    Article  PubMed  CAS  Google Scholar 

  157. Riant F, Roze E, Barbance C, Meneret A, Guyant-Marechal L, Lucas C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology. 2012;79(21):2122–4.

    Article  PubMed  CAS  Google Scholar 

  158. Michetti C, Castroflorio E, Marchionni I, Forte N, Sterlini B, Binda F, et al. The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations. Neurobiol Dis. 2017;99:66–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Berge OG. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol. 2011;164(4):1195–206.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. May A, Goadsby PJ. Pharmacological opportunities and pitfalls in the therapy of migraine. Curr Opin Neurol. 2001;14(3):341–5.

    Article  PubMed  CAS  Google Scholar 

  161. Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia. 1997;17(7):785–90.

    Article  PubMed  CAS  Google Scholar 

  162. Grazzi L, Sansone E, Raggi A, D'Amico D, De Giorgio A, Leonardi M, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Kojic Z, Stojanovic D. Pathophysiology of migraine—from molecular to personalized medicine. Med Pregl. 2013;66(1–2):53–7.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neurosciences, Huntington Medical Research Institutes (HMRI), Pasadena, CA, USA

    Xianghong Arakaki, Noah B. Gross, Alfred N. Fonteh & Michael G. Harrington

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  1. Xianghong Arakaki
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Correspondence to Xianghong Arakaki .

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  1. Department of Headache and Pain Medicine, Icahn School of Medicine at Mt. Sinai, Department of Headache and Pain Medicine, New York, NY, USA

    Mark W. Green

  2. Neurology & Neurological Sciences, Stanford School of Medicine Neurology & Neurological Sciences, Stanford, CA, USA

    Robert Cowan

  3. Department of Neurology, Medical College of Wisconsin, Department of Neurology, Milwaukee, WI, USA

    Frederick G. Freitag

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Arakaki, X., Gross, N.B., Fonteh, A.N., Harrington, M.G. (2019). Animal Models in Chronic Daily Headache (CDH) and Pathophysiology of CDH. In: Green, M., Cowan, R., Freitag, F. (eds) Chronic Headache. Springer, Cham. https://doi.org/10.1007/978-3-319-91491-6_21

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