Melih Zeki KAYA, Sibel BOZDAĞ PEHLİVAN, Levent ÖNER

Migren Araştırmalarında Kullanılan Güncel Hayvan Modelleri

Hayvan modelleri, insana zarar verme riski olmadan insanda görülen hastalıkların incelenmesinde ve yeni terapötik yaklaşımların geliştirilmesinde kullanılan önemli araştırma araçlarıdır. Hayvan modellerinde gözlenen biyolojik aktivite ile insanda elde edilen arasında her zaman birebir benzerlik olmasa da insan hastalıkları için birçok ilaç ve tedavi hayvan modellerinin rehberliğinde geliştirilmektedir. Bu kapsamda, son yıllarda baş ağrısı ve migren mekanizmalarını incelemek için hayvan modelleri yoğun bir şekilde geliştirilmiş ve bunun sonucu olarak migrenin anlaşılmasında ve anti migren tedavilerin geliştirilmesinde önemli adımlar atılmıştır. Bu modeller arasında, genetik modifikasyonlarla oluşturulan fare ve sıçan modelleri, trigeminal sinir sistemi aktivasyonunu taklit eden modeller ve inflamatuar ajanlarla baş ağrısı indüklenen modeller yer almaktadır. Her bir modelin kendine özgü üstünlük ve sınırlaması olduğundan, ilaç etkinliğini değerlendirmek için uygun hayvan modelinin seçimi ve sonuçların değerlendirilmesi için en uygun deneysel yöntemin seçimi kritik bir parametredir. Bu derlemede son yıllarda üzerinde yoğun bir biçimde çalışılan in-vivo migren modelleri ve bu modellerden elde edilen en son bulgular üzerinde tartışılacaktır

Anahtar Kelimeler:

Migren, Hayvan modelleri, Preklinik araştırmalar, Baş ağrısı, Nörobiyoloji

Current Animal Models Used in Migraine Research

Animal models are important research tools used in the study of human diseases and in the development of new therapeutic approaches without the risk of harming humans. Although there is not always one-to-one similarity between the biological activity observed in animal models and that obtained in humans, many drugs and treatments for human diseases are developed under the guidance of animal models. In this context, animal models have been extensively developed in recent years to examine the mechanisms of headache and migraine, and as a result, important steps have been taken in the understanding of migraine and the development of anti-migraine treatments. These models include mouse and rat models created by genetic modifications, models that mimic trigeminal nervous system activation, and models that induce headaches with inflammatory agents. Since each model has its own advantages and limitations, the selection of the appropriate animal model to evaluate drug efficacy and the most appropriate experimental method to evaluate the results is a critical parameter. In this review, in-vivo migraine models that have been studied extensively in recent years and the latest findings from these models will be discussed.

Keywords:

Migraine, Animal models, Preclinical studies, Headache, Neurobiology,

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1. Yildirim Ş, Akkoca Y, İNan LE. Migren ve Gerilim Tipi Baş Ağrısında Bilişsel-Davranışçı Tedavinin Kullanımı. Bilişsel Davranışçı Psikoterapi ve Araştırmalar Dergisi. 2015;4(1):10-7
2. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365-91.https://doi.org/10.1146/ annurev-physiol-030212-183717
3. Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015;35(17):6619- 29.https://doi.org/10.1523/jneurosci.0373-15.2015
4. Kissin I. Scientometrics of drug discovery efforts: pain-related molecular targets. Drug Des Devel Ther. 2015;9:3393-404. https://doi.org/10.2147/dddt.S85633
5. Thorlund K, Toor K, Wu P, Chan K, Druyts E, Ramos E, et al. Comparative tolerability of treatments for acute migraine: A network meta-analysis. Cephalalgia. 2017;37(10):965-78. https://doi.org/10.1177/0333102416660552
6. Chang DS, Hsu E, Hottinger DG, Cohen SP. Anti-nerve growth factor in pain management: current evidence. J Pain Res. 2016;9:373-83.https://doi.org/10.2147/jpr.S89061
7. Romero-Reyes M, Akerman S. Update on animal models of migraine. Curr Pain Headache Rep. 2014;18(11):462.https:// doi.org/10.1007/s11916-014-0462-z
8. Létienne R, Verscheure Y, John GW. Investigation of the effects of naratriptan, rizatriptan, and sumatriptan on jugular venous oxygen saturation in anesthetized pigs: implications for their mechanism of acute antimigraine action. J Pharmacol Exp Ther. 2003;307(1):168-74.https://doi.org/10.1124/ jpet.103.054940
9. Drummond PD, Lance JW. Extracranial vascular changes and the source of pain in migraine headache. Ann Neurol. 1983;13(1):32-7.https://doi.org/10.1002/ana.410130108
10. Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet. 1991;338(8758):13-7.https://doi. org/10.1016/0140-6736(91)90005-a
11. De Vries P, Villalón CM, Saxena PR. Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol. 1999;375(1-3):61-74.https:// doi.org/10.1016/s0014-2999(99)00197-1
12. Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia. 2004;24(8):611-22.https://doi.org/10.1111/j.1468- 2982.2003.00719.x
13. Den Boer MO, Van Woerkens LJ, Somers JA, Duncker DJ, Lachmann B, Saxena PR, et al. On the preservation and regulation of vascular tone in arteriovenous anastomoses during anesthesia. J Appl Physiol (1985). 1993;75(2):782-9.https:// doi.org/10.1152/jappl.1993.75.2.782
14. Kapoor K, Arulmani U, Heiligers JP, Garrelds IM, Willems EW, Doods H, et al. Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol. 2003;140(2):329-38.https://doi.org/10.1038/sj.bjp.0705451
15. Akerman S, Holland PR, Hoffmann J. Pearls and pitfalls in experimental in vivo models of migraine: dural trigeminovascular nociception. Cephalalgia. 2013;33(8):577-92.https://doi. org/10.1177/0333102412472071
16. Knyihár-Csillik E, Tajti J, Samsam M, Sáry G, Slezák S, Vécsei L. Effect of a serotonin agonist (sumatriptan) on the peptidergic innervation of the rat cerebral dura mater and on the expression of c-fos in the caudal trigeminal nucleus in an experimental migraine model. J Neurosci Res. 1997;48(5):449-64
17. Buzzi MG, Carter WB, Shimizu T, Heath H, 3rd, Moskowitz MA. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology. 1991;30(11):1193-200.https://doi.org/10.1016/0028- 3908(91)90165-8
18. 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.https://doi. org/10.1016/0143-4179(90)90114-e
19. 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.https://doi.org/10.1523/jneurosci. 0439-13.2013
20. Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol. 2012;72(4):559-63. https://doi.org/10.1002/ana.23653
21. Vila-Pueyo M, Strother LC, Kefel M, Goadsby PJ, Holland PR. Divergent influences of the locus coeruleus on migraine pathophysiology. Pain. 2019;160(2):385-94.https://doi. org/10.1097/j.pain.0000000000001421
22. 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.https://doi.org/10.1016/j.brainres. 2005.01.091
23. Akerman S, Karsan N, Bose P, Hoffmann JR, Holland PR, Romero- Reyes M, et al. Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity. Brain. 2019;142(1):103-19.https://doi.org/10.1093/brain/ awy313
24. Summ O, Charbit AR, Andreou AP, Goadsby PJ. Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain. 2010;133(9):2540-8.https://doi.org/10.1093/brain/awq224
25. 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.https://doi.org/10.1126/scitranslmed. aaa7557
26. Ramachandran R, Bhatt DK, Ploug KB, Olesen J, Jansen-Olesen I, Hay-Schmidt A, et al. A naturalistic glyceryl trinitrate infusion migraine model in the rat. Cephalalgia. 2012;32(1):73- 84.https://doi.org/10.1177/0333102411430855
27. Pedersen SH, Ramachandran R, Amrutkar DV, Petersen S, Olesen J, Jansen-Olesen I. Mechanisms of glyceryl trinitrate provoked mast cell degranulation. Cephalalgia. 2015;35(14):1287- 97.https://doi.org/10.1177/0333102415574846
28. Hougaard Pedersen S, Maretty L, Ramachandran R, Sibbesen JA, Yakimov V, Elgaard-Christensen R, et al. RNA Sequencing of Trigeminal Ganglia in Rattus Norvegicus after Glyceryl Trinitrate Infusion with Relevance to Migraine. PLoS One. 2016;11(5):e0155039.https://doi.org/10.1371/journal. pone.0155039
29. Ford AP. In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal. 2012;8(Suppl 1):3-26.https://doi.org/10.1007/s11302-011- 9271-6
30. 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.https://doi.org/10.1016/j. pain.2013.10.004
31. Ferrari LF, Levine JD, Green PG. Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat. Neuroscience. 2016;317:121-9.https://doi.org/10.1016/j.neuroscience. 2016.01.005
32. McGuinness BW, Harris EL. “Monday head”: an interesting occupational disorder. Br Med J. 1961;2(5254):745-7.https:// doi.org/10.1136/bmj.2.5254.745
33. Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain. 2014;137(Pt 11):2951-9.https://doi.org/10.1093/brain/ awu244
34. Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin- triggered migraine attacks. Brain. 2014;137(Pt 1):232-41. https://doi.org/10.1093/brain/awt320
35. 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.https://doi.org/10.1111/j.1468- 2982.2009.01864.x
36. Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, et al. Casein kinase iδ mutations in familial migraine and advanced sleep phase. Sci Transl Med. 2013;5(183):183ra56, 1-11.https://doi.org/10.1126/scitranslmed. 3005784
37. De Logu F, Landini L, Janal MN, Li Puma S, De Cesaris F, Geppetti P, et al. Migraine-provoking substances evoke periorbital allodynia in mice. J Headache Pain. 2019;20(1):18. https://doi.org/10.1186/s10194-019-0968-1
38. Cui Y, Toyoda H, Sako T, Onoe K, Hayashinaka E, Wada Y, et al. A voxel-based analysis of brain activity in high-order trigeminal pathway in the rat induced by cortical spreading depression. Neuroimage. 2015;108:17-22.https://doi.org/10.1016/j. neuroimage.2014.12.047
39. Cui Y, Takashima T, Takashima-Hirano M, Wada Y, Shukuri M, Tamura Y, et al. 11C-PK11195 PET for the in vivo evaluation of neuroinflammation in the rat brain after cortical spreading depression. J Nucl Med. 2009;50(11):1904-11.https://doi. org/10.2967/jnumed.109.066498
40. Ji RR, Chamessian A, Zhang YQ. Pain regulation by nonneuronal cells and inflammation. Science. 2016;354(6312):572- 7.https://doi.org/10.1126/science.aaf8924
41. Spong KE, Rodríguez EC, Robertson RM. Spreading depolarization in the brain of Drosophila is induced by inhibition of the Na+/K+-ATPase and mitigated by a decrease in activity of protein kinase G. J Neurophysiol. 2016;116(3):1152-60. https://doi.org/10.1152/jn.00353.2016
42. Haerter K, Ayata C, Moskowitz MA. Cortical Spreading Depression: A Model for Understanding Migraine Biology and Future Drug Targets. Headache Currents. 2005;2(5):97- 103.https://doi.org/https://doi.org/10.1111/j.1743- 5013.2005.00017.x
43. Biosa G, Bastianoni S, Rustici M. Chemical waves. Chemistry. 2006;12(13):3430-7.https://doi.org/10.1002/chem.200500929
44. Kunkler PE, Hulse RE, Schmitt MW, Nicholson C, Kraig RP. Optical current source density analysis in hippocampal organotypic culture shows that spreading depression occurs with uniquely reversing currents. J Neurosci. 2005;25(15):3952-61. https://doi.org/10.1523/jneurosci.0491-05.2005
45. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest. 2004;113(10):1447-55.https:// doi.org/10.1172/jci21227
46. Moskowitz MA. Genes, proteases, cortical spreading depression and migraine: impact on pathophysiology and treatment. Funct Neurol. 2007;22(3):133-6
47. Moskowitz MA, Nozaki K, Kraig RP. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci. 1993;13(3):1167-77. https://doi.org/10.1523/jneurosci.13-03-01167.1993
48. Liu CH, You Z, Ren J, Kim YR, Eikermann-Haerter K, Liu PK. Noninvasive delivery of gene targeting probes to live brains for transcription MRI. Faseb j. 2008;22(4):1193-203.https:// doi.org/10.1096/fj.07-9557com
49. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59(4):652-61.https://doi.org/10.1002/ ana.20778
50. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. 1994;117 ( Pt 1):199-210. https://doi.org/10.1093/brain/117.1.199
51. Kleeberg J, Petzold GC, Major S, Dirnagl U, Dreier JP. ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. Am J Physiol Heart Circ Physiol. 2004;286(4):H1339-46.https://doi. org/10.1152/ajpheart.00227.2003
52. Otori T, Greenberg JH, Welsh FA. Cortical spreading depression causes a long-lasting decrease in cerebral blood flow and induces tolerance to permanent focal ischemia in rat brain. J Cereb Blood Flow Metab. 2003;23(1):43-50.https://doi. org/10.1097/01.Wcb.0000035180.38851.38
53. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687-92.https://doi.org/10.1073/ pnas.071582498
54. Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, et al. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain. 2006;129(Pt 3):778-90.https://doi.org/10.1093/brain/awh716
55. Mayevsky A, Doron A, Manor T, Meilin S, Zarchin N, Ouaknine GE. Cortical spreading depression recorded from the human brain using a multiparametric monitoring system. Brain Res. 1996;740(1-2):268-74.https://doi.org/10.1016/s0006- 8993(96)00874-8
56. Milner PM. Note on a possible correspondence between the scotomas of migraine and spreading depression of Leão. Electroencephalogr Clin Neurophysiol. 1958;10(4):705.https://doi. org/10.1016/0013-4694(58)90073-7
57. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344-52.https://doi. org/10.1002/ana.410090406
58. Lauritzen M, Skyhøj Olsen T, Lassen NA, Paulson OB. Changes in regional cerebral blood flow during the course of classic migraine attacks. Ann Neurol. 1983;13(6):633-41.https://doi. org/10.1002/ana.410130609
59. PENFIELD W, McNAUGHTON F. DURAL HEADACHE AND INNERVATION OF THE DURA MATER. Archives of Neurology & Psychiatry. 1940;44(1):43-75.https://doi. org/10.1001/archneurpsyc.1940.02280070051003
60. Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-61.https://doi.org/10.1016/s1474- 4422(13)70067-x
61. May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab. 1999;19(2):115-27.https://doi. org/10.1097/00004647-199902000-00001
62. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12(10):570-84.https://doi.org/10.1038/nrn3057
63. 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(10):2825-33.https://doi.org/10.1111/j.1460- 9568.2006.05168.x
64. Liu Y, Broman J, Edvinsson L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res. 2008;1208:103-10.https://doi.org/10.1016/j.brainres. 2008.02.078
65. Melo-Carrillo A, Strassman AM, Nir RR, Schain AJ, Noseda R, Stratton J, et al. Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors. J Neurosci. 2017;37(44):10587-96.https://doi.org/10.1523/jneurosci. 2211-17.2017
66. Hu J, Milenkovic N, Lewin GR. The high threshold mechanotransducer: a status report. Pain. 2006;120(1-2):3-7.https://doi. org/10.1016/j.pain.2005.11.002
67. Charbit AR, Akerman S, Goadsby PJ. Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms. Pain. 2011;152(10):2365-76.https://doi.org/10.1016/j. pain.2011.07.002
68. Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia. 2015;35(14):1298-307. https://doi.org/10.1177/0333102415576723
69. Noseda R, Bernstein CA, Nir RR, Lee AJ, Fulton AB, Bertisch SM, et al. Migraine photophobia originating in cone-driven retinal pathways. Brain. 2016;139(Pt 7):1971-86.https://doi. org/10.1093/brain/aww119
70. Bloom FE. To spritz or not to spritz: the doubtful value of aimless iontophoresis. Life Sci. 1974;14(10):1819-34.https://doi. org/10.1016/0024-3205(74)90400-7
71. Donaldson C, Boers PM, Hoskin KL, Zagami AS, Lambert GA. The role of 5-HT1B and 5-HT1D receptors in the selective inhibitory effect of naratriptan on trigeminovascular neurons. Neuropharmacology. 2002;42(3):374-85.https://doi. org/10.1016/s0028-3908(01)00190-3
72. Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol. 2004;142(7):1171-81. https://doi.org/10.1038/sj.bjp.0705807
73. Shields KG, Goadsby PJ. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target? Neurobiol Dis. 2006;23(3):491- 501.https://doi.org/10.1016/j.nbd.2006.04.003
74. Thankachan S, Katsuki F, McKenna JT, Yang C, Shukla C, Deisseroth K, et al. Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice. Sci Rep. 2019;9(1):3607. https://doi.org/10.1038/s41598-019-40398-9
75. Bullitt E. Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol. 1990;296(4):517-30.https://doi.org/10.1002/ cne.902960402
76. Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T, Karin M. The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell. 1988;54(4):541-52. https://doi.org/10.1016/0092-8674(88)90076-1
77. Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV. Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc. Front Behav Neurosci. 2018;12:79.https://doi.org/10.3389/fnbeh.2018.00079
78. Coggeshall RE. Fos, nociception and the dorsal horn. Prog Neurobiol. 2005;77(5):299-352.https://doi.org/10.1016/j.pneurobio. 2005.11.002
79. Sundquist SJ, Nisenbaum LK. Fast Fos: rapid protocols for single- and double-labeling c-Fos immunohistochemistry in fresh frozen brain sections. J Neurosci Methods. 2005;141(1):9-20. https://doi.org/10.1016/j.jneumeth.2004.05.007
80. Morgan JI, Curran T. Calcium as a modulator of the immediate- early gene cascade in neurons. Cell Calcium. 1988;9(5- 6):303-11.https://doi.org/10.1016/0143-4160(88)90011-5
81. Harris JA. Using c-fos as a neural marker of pain. Brain Res Bull. 1998;45(1):1-8.https://doi.org/10.1016/s0361- 9230(97)00277-3
82. 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.https://doi.org/10.1111/j.1460- 9568.2006.05036.x
83. Hoskin KL, Bulmer DC, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by L-NAME. Neurosci Lett. 1999;266(3):173-6.https://doi.org/10.1016/s0304- 3940(99)00281-5
84. 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.https://doi. org/10.1016/0006-8993(95)00348-t
85. May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs. 2001;10(4):673-8.https://doi.org/10.1517/13543784.10.4.673
86. Shepheard SL, Williamson DJ, Williams J, Hill RG, Hargreaves RJ. Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in Dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats. Neuropharmacology. 1995;34(3):255-61.https://doi. org/10.1016/0028-3908(94)00153-j
87. Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature. 1987;328(6131):632-4.https://doi.org/10.1038/328632a0
88. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999;79(1):143-80.https:// doi.org/10.1152/physrev.1999.79.1.143
89. Martins-Oliveira M, Akerman S, Holland PR, Hoffmann JR, Tavares I, Goadsby PJ. Neuroendocrine signaling modulates specific neural networks relevant to migraine. Neurobiol Dis. 2017;101:16-26.https://doi.org/10.1016/j.nbd.2017.01.005
90. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55-63.https://doi. org/10.1016/0165-0270(94)90144-9
91. Minett MS, Quick K, Wood JN. Behavioral Measures of Pain Thresholds. Curr Protoc Mouse Biol. 2011;1(3):383-412. https://doi.org/10.1002/9780470942390.mo110116
92. Hansen JM, Thomsen LL, Olesen J, Ashina M. Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide. Cephalalgia. 2008;28(5):496-505.https://doi. org/10.1111/j.1468-2982.2008.01559.x
93. Farajdokht F, Mohaddes G, Shanehbandi D, Karimi P, Babri S. Ghrelin attenuated hyperalgesia induced by chronic nitroglycerin: CGRP and TRPV1 as targets for migraine management. Cephalalgia. 2018;38(11):1716-30.https://doi. org/10.1177/0333102417748563
94. Ben Aissa M, Tipton AF, Bertels Z, Gandhi R, Moye LS, Novack M, et al. Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia. 2018;38(8):1471- 84.https://doi.org/10.1177/0333102417737778
95. 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.https://doi.org/10.1002/ana.21537
96. Fioravanti B, Kasasbeh A, Edelmayer R, Skinner DP, Jr., Hartings JA, Burklund RD, et al. Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia. 2011;31(10):1090-100.https:// doi.org/10.1177/0333102411410609
97. Filiz A, Tepe N, Eftekhari S, Boran HE, Dilekoz E, Edvinsson L, et al. CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior. Cephalalgia. 2019;39(3):354-65.https://doi. org/10.1177/0333102417735845
98. Colburn RW, Lubin ML, Stone DJ, Jr., Wang Y, Lawrence D, D’Andrea MR, et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron. 2007;54(3):379-86.https://doi. org/10.1016/j.neuron.2007.04.017
99. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77-88.https://doi. org/10.1016/0304-3959(88)90026-7
100. Anderson EM, Mills R, Nolan TA, Jenkins AC, Mustafa G, Lloyd C, et al. Use of the Operant Orofacial Pain Assessment Device (OPAD) to measure changes in nociceptive behavior. J Vis Exp. 2013(76):e50336.https://doi.org/10.3791/50336