Deneysel Migren Modelleri
Özet
Migren, trigeminovasküler sistem, nörojenik inflamasyon ve santral duyarlılaşma gibi karmaşık mekanizmalarla ortaya çıkan, yaşam kalitesini ciddi şekilde etkileyen nörolojik bir hastalıktır. Bu mekanizmaları aydınlatmak ve yeni tedaviler geliştirmek için araştırmacılar, farklı yönleri taklit eden çok çeşitli deneysel hayvan modelleri kullanır. Bu bölümde, nitrogliserin veya CGRP uygulaması gibi tetikleyici modellerden, kortikal yayılan depolarizasyon ve genetik modellere kadar geniş bir yelpaze tanıtılmıştır. Her modelin, örneğin vasküler değişiklikleri, ağrı davranışını veya kronikleşme sürecini araştırmada kendine özgü güçlü yanları bulunmaktadır. Ancak, tür farklılıkları ve modelin klinik durumu ne ölçüde yansıttığı gibi sınırlamalar da dikkate alınmalıdır. Sonuç olarak, doğru soruyu sormak ve uygun modeli seçmek, migren gizeminin çözülmesindeki en kritik adımlardan biridir.
Migraine is a debilitating neurological disorder characterized by complex mechanisms involving the trigeminovascular system, neurogenic inflammation, and central sensitization. To decipher these mechanisms and develop novel therapies, researchers employ a wide array of experimental animal models, each mimicking distinct facets of the disease. This chapter reviews this spectrum, ranging from provocative models using nitroglycerin or CGRP administration to models of cortical spreading depression (CSD) and genetic (FHM) susceptibility. Each model offers unique strengths for investigating specific aspects, such as vascular changes, pain-related behaviour, or chronification processes. However, their limitations, including species differences and translational validity, must be carefully considered. Ultimately, asking the right question and selecting the appropriate model remain pivotal steps in unraveling the enigma of migraine.
Referanslar
Pensato U, Cevoli S, Pierangeli G, Cortelli P. The evolutionary meaning of migraine. Cephalalgia. 2023 Dec 1;43(12):03331024231209303.
Begasse de Dhaem O, Burch R, Rosen N, Shubin Stein K, Loder E, Shapiro RE. Workforce Gap Analysis in the Field of Headache Medicine in the United States. Headache: The Journal of Head and Face Pain. 2020;60(2):478–81.
Ettlin DA. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808.
Lipton RB, Silberstein SD. Episodic and Chronic Migraine Headache: Breaking Down Barriers to Optimal Treatment and Prevention. Headache: The Journal of Head and Face Pain. 2015;55(S2):103–22.
Al-Hassany L, Haas J, Piccininni M, Kurth T, Maassen Van Den Brink A, Rohmann JL. Giving Researchers a Headache - Sex and Gender Differences in Migraine. Front Neurol. 2020;11:549038.
Grangeon L, Lange KS, Waliszewska-Prosół M, Onan D, Marschollek K, Wiels W, et al. Genetics of migraine: where are we now? J Headache Pain. 2023 Feb 20;24(1):12.
Sureda-Gibert P, Romero-Reyes M, Akerman S. Nitroglycerin as a model of migraine: Clinical and preclinical review. Neurobiology of Pain. 2022 Aug 1;12:100105.
Thomsen L l., Kruuse C, Iversen H k., Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. European Journal of Neurology. 1994;1(1):73–80.
Zhang X, Kainz V, Zhao J, Strassman AM, Levy D. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Annals of Neurology. 2013;73(6):741–50.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010 Oct 1;30(10):1179–86.
Wattiez AS, Sowers LP, Russo AF. Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting. Expert Opinion on Therapeutic Targets. 2020 Feb 1;24(2):91–100.
Song X, Zhu Q, Zhang J, Yang J, Zhang X, Song Q. Trigeminal nerve-driven neurogenic inflammation linking migraine to glioblastoma invasion: a literature review. Front Immunol. 2025;16:1632154.
Maassenvandenbrink A, Chan KY. Neurovascular pharmacology of migraine. Eur J Pharmacol. 2008 May 13;585(2–3):313–9.
Biscetti L, Cresta E, Cupini LM, Calabresi P, Sarchielli P. The putative role of neuroinflammation in the complex pathophysiology of migraine: From bench to bedside. Neurobiology of Disease. 2023 May 1;180:106072.
Salahi M, Parsa S, Nourmohammadi D, Razmkhah Z, Salimi O, Rahmani M, et al. Immunologic aspects of migraine: A review of literature. Front Neurol. 2022 Sept 28;13:944791.
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine. PAIN. 2017 Apr;158(4):543.
Gupta S, Mehrotra S, Villalón CM, Garrelds IM, de Vries R, van Kats JP, et al. Characterisation of CGRP receptors in human and porcine isolated coronary arteries: evidence for CGRP receptor heterogeneity. Eur J Pharmacol. 2006 Jan 13;530(1–2):107–16.
Goadsby PJ, Lipton RB, Ferrari MD. Migraine--current understanding and treatment. N Engl J Med. 2002 Jan 24;346(4):257–70.
Gupta S, Bhatt D, Boni L, Olesen J. Improvement of the Closed Cranial Window Model in Rats by Intracarotid Infusion of Signalling Molecules Implicated in Migraine. Cephalalgia. 2010 Jan 1;30(1):27–36.
Cutrer FM, Yu XJ, Ayata G, Moskowitz MA, Waeber C. Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis. Neuropharmacology. 1999 July 1;38(7):1043–53.
Spekker E, Laborc KF, Bohár Z, Nagy-Grócz G, Fejes-Szabó A, Szűcs M, et al. Effect of dural inflammatory soup application on activation and sensitization markers in the caudal trigeminal nucleus of the rat and the modulatory effects of sumatriptan and kynurenic acid. J Headache Pain. 2021 Mar 31;22(1):17.
Lukács M, Warfvinge K, Tajti J, Fülöp F, Toldi J, Vécsei L, et al. Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72). J Headache Pain. 2017 Mar 23;18(1):39.
Sureda-Gibert P, Romero-Reyes M, Akerman S. Nitroglycerin as a model of migraine: Clinical and preclinical review. Neurobiology of Pain. 2022 Aug 1;12:100105.
Lewter LA, Arnold RL, Narosov NB, Dussor G, Kolber BJ. Sex differences in the effects of calcitonin gene-related peptide signaling on migraine-like behavior in animal models: a narrative review. Front Neurol. 2025 July 10;16:1603758.
Wattiez AS, Wang M, Russo AF. CGRP in Animal Models of Migraine. Handb Exp Pharmacol. 2019;255:85–107.
Vitale M, Tottene A, Zarin Zadeh M, Brennan K, Pietrobon D. Mechanisms of initiation of cortical spreading depression. J Headache Pain. 2023 Aug 8;24(1):105.
Jin X, Morais A, Sasaki Y, Zhai Q, Banerjee P, Harriott A, et al. Small-molecule CGRP antagonist atogepant does not affect cortical spreading depression susceptibility in rats. J Headache Pain. 2025 Aug 5;26(1):177.
Chung DY, Sadeghian H, Qin T, Lule S, Lee H, Karakaya F, et al. Determinants of Optogenetic Cortical Spreading Depolarizations. Cereb Cortex. 2019 Mar 1;29(3):1150–61.
Kudo C, Toyama M, Boku A, Hanamoto H, Morimoto Y, Sugimura M, et al. Anesthetic effects on susceptibility to cortical spreading depression. Neuropharmacology. 2013 Apr 1;67:32–6.
Takizawa T, Qin T, Lopes de Morais A, Sugimoto K, Chung JY, Morsett L, et al. Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex. J Cereb Blood Flow Metab. 2020 May 1;40(5):1117–31.
Dehghani A, Karatas H. Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology. Curr Neuropharmacol. 2019 Oct;17(10):961–73.
Ma Z, Li C, Bai W, Xie W, Zhang M, Xiao H, et al. Induction of more severe central sensitization in a medication overuse headache model mice through active ingestion of rizatriptan. J Headache Pain. 2025 May 20;26(1):123.
Greco R, Demartini C, Zanaboni AM, Tassorelli C. Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing. J Headache Pain. 2018 July 13;19(1):51.
