Neuroanatomical evidence and a mouse calcitonin gene-related peptide model in line with human functional magnetic resonance imaging data support the involvement of peptidergic Edinger-Westphal nucleus in migraine.
Journal
Pain
ISSN: 1872-6623
Titre abrégé: Pain
Pays: United States
ID NLM: 7508686
Informations de publication
Date de publication:
14 Jun 2024
14 Jun 2024
Historique:
received:
16
12
2023
accepted:
02
05
2024
medline:
14
6
2024
pubmed:
14
6
2024
entrez:
14
6
2024
Statut:
aheadofprint
Résumé
The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene-related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). Tracing study examined connection between EWcp and the spinal trigeminal nucleus (STN). The intraperitoneal CGRP injection model of migraine was applied and validated by light-dark box, and von Frey assays in mice, in situ hybridization combined with immunostaining, were used to assess the functional-morphological changes. The functional connectivity matrix of EW was examined using functional magnetic resonance imaging in control humans and interictal migraineurs. We proved the expression of CGRP receptor components in both murine and human DRN and EWcp. We identified a direct urocortinergic projection from EWcp to the STN. Photophobic behavior, periorbital hyperalgesia, increased c-fos gene-encoded protein immunoreactivity in the lateral periaqueductal gray matter and trigeminal ganglia, and phosphorylated c-AMP-responsive element binding protein in the STN supported the efficacy of CGRP-induced migraine-like state. Calcitonin gene-related peptide administration also increased c-fos gene-encoded protein expression, Ucn1 mRNA, and peptide content in EWcp/UCN1 neurons while reducing serotonin and tryptophan hydroxylase-2 levels in the DRN. Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.
Identifiants
pubmed: 38875125
doi: 10.1097/j.pain.0000000000003294
pii: 00006396-990000000-00627
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.
Références
Al-Omari A, Kecskés M, Gaszner B, Biró-Sütő T, Fazekas B, Berta G, Kuzma M, Pintér E, Kormos V. Functionally active TRPA1 ion channel is downregulated in peptidergic neurons of the Edinger-Westphal nucleus upon acute alcohol exposure. Front Cell Dev Biol 2023;10:1046559.
Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning Pvd, Larsson HBW, Olesen J, Ashina M. Evidence for a vascular factor in migraine. Ann Neurol 2011;69:635–45.
Ashina M, Hansen JM, Á Dunga BO, Olesen J. Human models of migraine—short-term pain for long-term gain. Nat Rev Neurol 2017;13:713–24.
Ashina H, Schytz HW, Ashina M. CGRP in human models of migraine. Handb Exp Pharmacol 2019;255:109–20.
Avona A, Mason BN, Lackovic J, Wajahat N, Motina M, Quigley L, Burgos-Vega C, Moldovan Loomis C, Garcia-Martinez LF, Akopian AN, Price TJ, Dussor G. Repetitive stress in mice causes migraine-like behaviors and calcitonin gene-related peptide-dependent hyperalgesic priming to a migraine trigger. PAIN 2020;161:2539–50.
Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 2002;22:193–9.
Bale TL, Lee KF, Vale WW. The role of corticotropin-releasing factor receptors in stress and anxiety. Integr Comp Biol 2002;42:552–5.
Bartsch T, Goadsby PJ. Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain 2003;126:1801–13.
Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI, Ptáček LJ, Ahn AH. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 2010;30:170–8.
Benemei S, De Logu F, Li Puma S, Marone IM, Coppi E, Ugolini F, Liedtke W, Pollastro F, Appendino G, Geppetti P, Materazzi S, Nassini R. The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. Br J Pharmacol 2017;174:2897–911.
Bhatt DK, Gupta S, Ploug KB, Jansen-Olesen I, Olesen J. MRNA distribution of CGRP and its receptor components in the trigeminovascular system and other pain related structures in rat brain, and effect of intracerebroventricular administration of CGRP on Fos expression in the TNC. Neurosci Lett 2014;559:99–104.
Bhatt DK, Ramachandran R, Christensen SL, Gupta S, Jansen-Olesen I, Olesen J. CGRP infusion in unanesthetized rats increases expression of c-Fos in the nucleus tractus solitarius and caudal ventrolateral medulla, but not in the trigeminal nucleus caudalis. Cephalalgia 2015;35:220–33.
Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004;84:903–34.
Chalmers DT, Lovenberg TW, De Souza EB. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci 1995;15:6340–50.
De Souza EB, Insel TR, Perrin MH, Rivier J, Vale WW, Kuhar MJ. Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study. J Neurosci 1985;5:3189–203.
de Vries T, MaassenVanDenBrink A. CGRP-targeted antibodies in difficult-to-treat migraine. Nat Rev Neurol 2019;15:688–9.
Deen M, Hansen HD, Hougaard A, Nørgaard M, Eiberg H, Lehel S, Ashina M, Knudsen GM. High brain serotonin levels in migraine between attacks: a 5-HT4 receptor binding PET study. Neuroimage Clin 2018;18:97–102.
Derks NM, Roubos EW, Kozicz T. Presence of estrogen receptor β in urocortin 1-neurons in the mouse non-preganglionic Edinger-Westphal nucleus. Gen Comp Endocrinol 2007;153:228–34.
Derks NM, Gaszner B, Roubos EW, Kozicz LT. Sex differences in urocortin 1 dynamics in the non-preganglionic Edinger-Westphal nucleus of the rat. Neurosci Res 2010;66:117–23.
Dickerson IM. Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. Curr Protein Pept Sci 2013;14:407–15.
Ding SL, Royall JJ, Sunkin SM, Ng L, Facer BAC, Lesnar P, Guillozet-Bongaarts A, McMurray B, Szafer A, Dolbeare TA, Stevens A, Tirrell L, Benner T, Caldejon S, Dalley RA, Dee N, Lau C, Nyhus J, Reding M, Riley ZL, Sandman D, Shen E, van der Kouwe A, Varjabedian A, Wright M, Zollei L, Dang C, Knowles JA, Koch C, Phillips JW, Sestan N, Wohnoutka P, Zielke HR, Hohmann JG, Jones AR, Bernard A, Hawrylycz MJ, Hof PR, Fischl B, Lein ES. Comprehensive cellular-resolution atlas of the adult human brain. J Comp Neurol 2016;524:3127–481.
Donner NC, Davies SM, Fitz SD, Kienzle DM, Shekhar A, Lowry CA. Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2020;96:109730.
Dos Santos Júnior ED, Da Silva AV, Da Silva KRT, Haemmerle CAS, Batagello DS, Da Silva JM, Lima LB, Da Silva RJ, Diniz GB, Sita LV, Elias CF, Bittencourt JC. The centrally projecting Edinger-Westphal nucleus-I: efferents in the rat brain. J Chem Neuroanat 2015;68:22–38.
Drummond PD. Tryptophan depletion increases nausea, headache and photophobia in migraine sufferers. Cephalalgia 2006;26:1225–33.
Durham PL. Diverse physiological roles of calcitonin gene-related peptide in migraine pathology: modulation of neuronal-glial-immune cells to promote peripheral and central sensitization. Curr Pain Headache Rep 2016;20:48.
Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, Grant PE, Greer DM, Greenberg SM, Kinney HC, Folkerth RD. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012;71:531–46.
Edvinsson L, Grell AS, Warfvinge K. Expression of the CGRP family of neuropeptides and their receptors in the trigeminal ganglion. J Mol Neurosci 2020;70:930–44.
Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol 2015;80:193–9.
Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 2017;57(suppl 2):47–55.
Farkas S, Bölcskei K, Markovics A, Varga A, Kis-Varga Á, Kormos V, Gaszner B, Horváth C, Tuka B, Tajti J, Helyes Z. Utility of different outcome measures for the nitroglycerin model of migraine in mice. J Pharmacol Toxicol Methods 2016;77:33–44.
Fehér M, Márton Z, Szabó Á, Kocsa J, Kormos V, Hunyady Á, Kovács LÁ, Ujvári B, Berta G, Farkas J, Füredi N, Gaszner T, Pytel B, Reglődi D, Gaszner B. Downregulation of PACAP and the PAC1 receptor in the basal ganglia, substantia nigra and centrally projecting Edinger–Westphal nucleus in the rotenone model of Parkinson's disease. Int J Mol Sci 2023;24:11843.
Fekete ÉM, Inoue K, Zhao Y, Rivier JE, Vale WW, Szücs A, Koob GF, Zorrilla EP. Delayed satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food intake by prolonging the post-meal interval. Neuropsychopharmacology 2007;32:1052–68.
Fox JH, Lowry CA. Corticotropin-releasing factor-related peptides, serotonergic systems, and emotional behavior. Front Neurosci 2013;7:169.
Gaszner B, Csernus V, Kozicz T. Urocortinergic neurons respond in a differentiated manner to various acute stressors in the Edinger-Westphal nucleus in the rat. J Comp Neurol 2004;480:170–9.
Gaszner B, Van Wijk DCWA, Korosi A, Józsa R, Roubos EW, Kozicz T. Diurnal expression of period 2 and urocortin 1 in neurons of the non-preganglionic Edinger-Westphal nucleus in the rat. Stress 2009;12:115–24.
Gaszner B, Kormos V, Kozicz T, Hashimoto H, Reglodi D, Helyes Z. The behavioral phenotype of pituitary adenylate-cyclase activating polypeptide-deficient mice in anxiety and depression tests is accompanied by blunted c-Fos expression in the bed nucleus of the stria terminalis, central projecting Edinger-Westphal nucleus, ventral lateral septum, and dorsal raphe nucleus. Neuroscience 2012;202:283–99.
Gecse K, Dobos D, Aranyi CS, Galambos A, Baksa D, Kocsel N, Szabó E, Pap D, Virág D, Ludányi K, Kökönyei G, Emri M, Bagdy G, Juhasz G. Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients. Sci Rep 2022;12:739.
Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993;33:48–56.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183–7.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30:1179–86.
Harriott AM, Strother LC, Vila-Pueyo M, Holland PR. Animal models of migraine and experimental techniques used to examine trigeminal sensory processing. J Headache Pain 2019;20:91.
Henson B, Hollingsworth H, Nevois E, Herndon C. Calcitonin gene-related peptide (CGRP) antagonists and their use in migraines. J Pain Palliat Care Pharmacother 2020;34:22–31.
Huang D, Grady FS, Peltekian L, Laing JJ, Geerling JC. Efferent projections of CGRP/Calca-expressing parabrachial neurons in mice. J Comp Neurol 2021;529:2911–57.
Im E. Multi-facets of corticotropin-releasing factor in modulating inflammation and angiogenesis. J Neurogastroenterol Motil 2015;21:25–32.
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. PAIN 2017;158:543–59.
Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in migraine. Headache 2019;59:659–81.
Jacobs B, Dussor G. Neurovascular contributions to migraine: moving beyond vasodilation. Neuroscience 2016;338:130–44.
Jia Z, Yu S. Grey matter alterations in migraine: a systematic review and meta-analysis. Neuroimage Clin 2017;14:130–40.
Jiang W, Li Z, Wei N, Chang W, Chen W, Sui HJ. Effectiveness of physical therapy on the suboccipital area of patients with tension-type headache: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 2019;98:e15487.
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack. Cephalalgia 2005;25:179–83.
Jung A, Huge A, Kuhlenbäumer G, Kempt S, Seehafer T, Evers S, Berger K, Marziniak M. Genetic TPH2 variants and the susceptibility for migraine: association of a TPH2 haplotype with migraine without aura. J Neural Transm 2010;117:1253–60.
Kaiser EA, Kuburas A, Recober A, Russo AF. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT1B/D agonist. J Neurosci 2012;32:15439–49.
Kim SJ, Yeo JH, Yoon SY, Kwon SG, Lee JH, Beitz AJ, Roh DH. Differential development of facial and hind paw allodynia in a nitroglycerin-induced mouse model of chronic migraine: role of capsaicin sensitive primary afferents. Biol Pharm Bull 2018;41:172–81.
Kormos V, Gaszner B. Role of neuropeptides in anxiety, stress, and depression: from animals to humans. Neuropeptides 2013;47:401–19.
Kormos V, Kecskés A, Farkas J, Gaszner T, Csernus V, Alomari A, Hegedüs D, Renner É, Palkovits M, Zelena D, Helyes Z, Pintér E, Gaszner B. Peptidergic neurons of the Edinger-Westphal nucleus express TRPA1 ion channel that is downregulated both upon chronic variable mild stress in male mice and in humans who died by suicide. J Psychiatry Neurosci 2022;47:E162–75.
Kozicz T, Li M, Arimura A. The activation of urocortin immunoreactive neurons in the Edinger-Westphal nucleus following acute pain stress in rats. Stress 2001;4:85–90.
Kozicz T, Bittencourt JC, May PJ, Reiner A, Gamlin PDR, Palkovits M, Horn AKE, Toledo CAB, Ryabinin AE. The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 2011;519:1413–34.
Kozicz T. Neurons colocalizing urocortin and cocaine and amphetamine-regulated transcript immunoreactivities are induced by acute lipopolysaccharide stress in the Edinger-Westphal nucleus in the rat. Neuroscience 2003;116:315–20.
Kozicz T. On the role of urocortin 1 in the non-preganglionic Edinger-Westphal nucleus in stress adaptation. Gen Comp Endocrinol 2007;153:235–40.
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia 2002;22:54–61.
Li J, Ryabinin AE. Oxytocin receptors in the mouse centrally-projecting Edinger-Westphal nucleus and their potential functional significance for thermoregulation. Neuroscience 2022;498:93–104.
Lipton RB, Bigal ME, Rush SR, Yenkosky JP, Liberman JN, Bartleson JD, Silberstein SD. Migraine practice patterns among neurologists. Neurology 2004;62:1926–31.
Lukkes JL, Staub DR, Dietrich A, Truitt W, Neufeld-Cohen A, Chen A, Johnson PL, Shekhar A, Lowry CA. Topographical distribution of corticotropin-releasing factor type 2 receptor-like immunoreactivity in the rat dorsal raphe nucleus: Co-localization with tryptophan hydroxylase. Neuroscience 2011;183:47–63.
Ma W, Chabot JG, Powell KJ, Jhamandas K, Dickerson IM, Quirion R. Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience 2003;120:677–94.
Maciewicz R, Phipps BS, Foote WE, Aronin N, DiFiglia M. The distribution of substance P-containing neurons in the cat Edinger-Westphal nucleus: relationship to efferent projection systems. Brain Res 1983;270:217–30.
Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, Szabadfi K, Tuka B, Tajti J, Szolcsanyi J, Pinter E, Hashimoto H, Kun J, Reglodi D, Helyes Z. Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis 2012;45:633–44.
Marziniak M, Kienzler C, Kuhlenbäumer G, Sommer C, Mössner R. Functional gene variants of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 in migraine. J Neural Transm 2009;116:815–9.
Mason BN, Kaiser EA, Kuburas A, Loomis MCM, Latham JA, Garcia-Martinez LF, Russo AF. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms. J Neurosci 2017;37:204–16.
Mason BN, Wattiez AS, Balcziak LK, Kuburas A, Kutschke WJ, Russo AF. Vascular actions of peripheral CGRP in migraine-like photophobia in mice. Cephalalgia 2020;40:1585–604.
Messlinger K. The big CGRP flood - sources, sinks and signaling sites in the trigeminovascular system. J Headache Pain 2018;19:22.
Miller S, Liu H, Warfvinge K, Shi L, Dovlatyan M, Xu C, Edvinsson L. Immunohistochemical localization of the calcitonin gene-related peptide binding site in the primate trigeminovascular system using functional antagonist antibodies. Neuroscience 2016;328:165–83.
Mitsikostas DD, Knight YE, Lasalandra M, Kavantzas N, Goadsby PJ. Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization? J Headache Pain 2011;12:411–7.
Napadow V, Sclocco R, Henderson LA. Brainstem neuroimaging of nociception and pain circuitries. Pain Rep 2019;4:e745.
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM; BIBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene–related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;350:1104–10.
Olesen J. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1–211.
Ong WY, Stohler CS, Herr DR. Role of the prefrontal cortex in pain processing. Mol Neurobiol 2019;56:1137–66.
Paxinos G. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic Press, 2001. p. 105–120.
Priest MF, Freda SN, Badong D, Dumrongprechachan V, Kozorovitskiy Y. Peptidergic modulation of fear responses by the Edinger-Westphal nucleus. bioRxiv 2021;2021.08.05.455317.
Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med 2011;13:e36.
Razeghi Jahromi S, Togha M, Ghorbani Z, Hekmatdoost A, Khorsha F, Rafiee P, Shirani P, Nourmohammadi M, Ansari H. The association between dietary tryptophan intake and migraine. Neurol Sci 2019;40:2349–55.
Rea BJ, Wattiez AS, Waite JS, Castonguay WC, Schmidt CM, Fairbanks AM, Robertson BR, Brown CJ, Mason BN, Moldovan-Loomis MC, Garcia-Martinez LF, Poolman P, Ledolter J, Kardon RH, Sowers LP, Russo AF. Peripherally administered calcitonin gene-related peptide induces spontaneous pain in mice: implications for migraine. PAIN 2018;159:2306–17.
Rorden C, Brett M. Stereotaxic display of brain lesions. Behav Neurol 2000;12:191–200.
Rossi MF, Tumminello A, Marconi M, Gualano MR, Santoro PE, Malorni W, Moscato U. Sex and gender differences in migraines: a narrative review. Neurol Sci 2022;43:5729–34.
Rouwette T, Klemann K, Gaszner B, Scheffer GJ, Roubos EW, Scheenen WJJM, Vissers K, Kozicz T. Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain. Neuroscience 2011;183:15–24.
Sakai Y, Dobson C, Diksic M, Aubé M, Hamel E. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 2008;70:431–9.
Salvatore CA, Mallee JJ, Bell IM, Zartman CB, Williams TM, Koblan KS, Kane SA. Identification and pharmacological characterization of domains involved in binding of CGRP receptor antagonists to the calcitonin-like receptor. Biochemistry 2006;45:1881–7.
Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika 1965;52:591.
Shibata Y. Migraine pathophysiology revisited: proposal of a new molecular theory of migraine pathophysiology and headache diagnostic criteria. Int J Mol Sci 2022;23:13002.
Skorobogatykh K, Van Hoogstraten WS, Degan D, Prischepa A, Savitskaya A, Ileen BM, Bentivegna E, Skiba I, D'Acunto L, Ferri L, Sacco S, Hansen JM, Amin FM; European Headache Federation School of Advanced Studies EHF-SAS. Functional connectivity studies in migraine: what have we learned? J Headache Pain 2019;20:108.
Smith GST, Savery D, Marden C, López Costa JJ, Averill S, Priestley JV, Rattray M. Distribution of messenger RNAs encoding enkephalin, substance P, somatostatin, galanin, vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene-related peptide in the midbrain periaqueductal grey in the rat. J Comp Neurol 1994;350:23–40.
Spina MG, Langnaese K, Orlando GF, Horn TFW, Rivier J, Vale WW, Wolf G, Engelmann M. Colocalization of urocortin and neuronal nitric oxide synthase in the hypothalamus and Edinger-Westphal nucleus of the rat. J Comp Neurol 2004;479:271–86.
Szekeres-Paraczky C, Szocsics P, Erőss L, Fabó D, Mód L, Maglóczky Z. Reorganization of parvalbumin immunopositive perisomatic innervation of principal cells in focal cortical dysplasia type IIB in human epileptic patients. Int J Mol Sci 2022;23:4746.
Tang Y, Liu S, Shu H, Yanagisawa L, Tao F. Gut microbiota dysbiosis enhances migraine-like pain via TNFα upregulation. Mol Neurobiol 2020;57:461–8.
Tepper SJ. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache 2018;58(suppl 3):276–90.
Ujvári B, Pytel B, Márton Z, Bognár M, Kovács LÁ, Farkas J, Gaszner T, Berta G, Kecskés A, Kormos V, Farkas B, Füredi N, Gaszner B. Neurodegeneration in the centrally-projecting Edinger-Westphal nucleus contributes to the non-motor symptoms of Parkinson's disease in the rat. J Neuroinflammation 2022;19:31.
Valentino RJ, Lucki I, Van Bockstaele E. Corticotropin-releasing factor in the dorsal raphe nucleus: linking stress coping and addiction. Brain Res 2010;1314:29–37.
van der Doelen RHA, Robroch B, Arnoldussen IA, Schulpen M, Homberg JR, Kozicz T. Serotonin and urocortin 1 in the dorsal raphe and Edinger–Westphal nuclei after early life stress in serotonin transporter knockout rats. Neuroscience 2017;340:345–58.
Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995;378:287–92.
Vila-Pueyo M, Hoffmann J, Romero-Reyes M, Akerman S. Brain structure and function related to headache: brainstem structure and function in headache. Cephalalgia 2019;39:1635–60.
Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003;299:76.
Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, Wu X, Vo HT, Ma XJ, Luo Y. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 2012;14:22–29.
Wang S, Wang H, Zhao D, Liu X, Yan W, Wang M, Zhao R. Grey matter changes in patients with vestibular migraine. Clin Radiol 2019;74:898.e1–e5.
Waselus M, Nazzaro C, Valentino RJ, Van Bockstaele EJ. Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol Psychiatry 2009;66:76–83.
Wattiez AS, Wang M, Russo AF. CGRP in animal models of migraine. Handb Exp Pharmacol 2019;255:85–107.
Wiley RG, Kline IV RH. Neuronal lesioning with axonally transported toxins. J Neurosci Methods 2000;103:73–82.
Wood AJJ, Welch KMA. Drug therapy of migraine. N Engl J Med 1993;329:1476–83.
Xu L, Füredi N, Lutter C, Geenen B, Pétervári E, Balaskó M, Dénes Á, Kovács KJ, Gaszner B, Kozicz T. Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats. Neuropharmacology 2022;205:108898.
You Y, Park JS. A novel human brainstem map based on true-color sectioned images. J Korean Med Sci 2023;38:e76.
Zuniga A, Ryabinin AE. Involvement of centrally projecting Edinger-Westphal nucleus neuropeptides in actions of addictive drugs. Brain Sci 2020;10:67.