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The Journal of Headache and Pain

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Open Access 01-12-2017 | Research article

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

Authors: M. Lukács, K. Warfvinge, J. Tajti, F. Fülöp, J. Toldi, L. Vécsei, L. Edvinsson

Published in: The Journal of Headache and Pain | Issue 1/2017

Abstract

Background

Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund’s Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.

Methods

Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C₁-C₂ regions of the spinal cord.

Results

We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C₁-C₂ neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.

Conclusion

This is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.

Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P (2015) Headache disorders are third cause of disability worldwide. J Headache Pain 16:58CrossRefPubMedPubMedCentral

Global Burden of Disease Study 2013 Collaborators. Global (2015) regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386(9995):743–800

Manack AN, Buse DC, Lipton RB (2011) Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep 15(1):70–78CrossRefPubMed

Moskowitz MA (2008) Defining a pathway to discovery from bench to bedside: the trigeminovascular system and sensitization. Headache 48(5):688–690CrossRefPubMed

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

Edvinsson L (2011) Tracing neural connections to pain pathways with relevance to primary headaches. Cephalalgia 31(6):737–747CrossRefPubMed

Liu Y, Broman J, Zhang M, Edvinsson L (2009) Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia 29(9):935–948CrossRefPubMed

Noseda R, Burstein R, (2013) Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain 154(Suppl1):1–21

Goadsby PJ (2005) Migraine, allodynia, sensitisation and all of that. Eur Neurol 53(Suppl 1):10–16CrossRefPubMed

10.

Burstein R, Jakubowski M (2004) Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol 55(1):27–36CrossRefPubMed

11.

Bartsch T, Goadsby PJ (2003) Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain 126(Pt 8):1801–1813CrossRefPubMed

12.

Curto M, Lionetto L, Negro A, Capi M, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P (2015) Altered kynurenine pathway metabolites in serum of chronic migraine patients. J Headache Pain 17(1):47CrossRefPubMed

13.

Curto M, Lionetto L, Negro A, Capi M, Perugino F, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P (2015) Altered serum levels of kynurenine metabolites in patients affected by cluster headache. J Headache Pain 17:27CrossRefPubMed

14.

Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR (1991) Blood–brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 56(6):2007–2017CrossRefPubMed

15.

Fulop F, Szatmari I, Toldi J, Vecsei L (2012) Modifications on the carboxylic function of kynurenic acid. J Neural Transm (Vienna) 119(2):109–114CrossRef

16.

Lukacs M, Haanes KA, Majlath Z, Tajti J, Vecsei L, Warfvinge K, Edvinsson L (2015) Dural administration of inflammatory soup or Complete Freund’s Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion. J Headache Pain 16:564CrossRefPubMed

17.

Lukacs M, Warfvinge K, Kruse LS, Tajti J, Fulop F, Toldi J, Vecsei L, Edvinsson L (2016) KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1beta in the rat trigeminal ganglion. J Headache Pain 17(1):64CrossRefPubMedPubMedCentral

18.

Vieira DS, Naffah-Mazzacoratti Mda G, Zukerman E, Senne Soares CA, Cavalheiro EA, Peres MF (2007) Glutamate levels in cerebrospinal fluid and triptans overuse in chronic migraine. Headache 47(6):842–847CrossRefPubMed

19.

Kaszaki J, Erces D, Varga G, Szabo A, Vecsei L, Boros M (2012) Kynurenines and intestinal neurotransmission: the role of N-methyl-D-aspartate receptors. J Neural Transm (Vienna) 119(2):211–223CrossRef

20.

Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L (1600) Localization of CGRP, CGRP receptor PACAP and glutamate in trigeminal ganglion Relation to the blood–brain barrier. Brain Res 2015:93–109

21.

Stoyanova I, Dandov A, Lazarov N, Chouchkov C (1998) GABA- and glutamate-immunoreactivity in sensory ganglia of cat: a quantitative analysis. Arch Physiol Biochem 106(5):362–369CrossRefPubMed

22.

Kung LH, Gong K, Adedoyin M, Ng J, Bhargava A, Ohara PT, Jasmin L (2013) Evidence for glutamate as a neuroglial transmitter within sensory ganglia. PLoS One 8(7):e68312CrossRefPubMedPubMedCentral

23.

Vecsei L, Szalardy L, Fulop F, Toldi J (2013) Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12(1):64–82CrossRefPubMed

24.

Vamos E, Pardutz A, Klivenyi P, Toldi J, Vecsei L (2009) The role of kynurenines in disorders of the central nervous system: possibilities for neuroprotection. J Neurol Sci 283(1–2):21–27CrossRefPubMed

25.

Curto M, Lionetto L, Fazio F, Mitsikostas DD, Martelletti P (2015) Fathoming the kynurenine pathway in migraine: why understanding the enzymatic cascades is still critically important. Intern Emerg Med 10(4):413–421CrossRefPubMed

26.

Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ, Croitoru J, Brew BJ (2001) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 78(4):842–853CrossRefPubMed

27.

Lee DY, Lee KS, Lee HJ, Noh YH, Kim do H, Lee JY, Cho SH, Yoon OJ, Lee WB, Kim KY, Chung YH, Kim SS (2008) Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway. Eur J Cell Biol 87(6):389–397CrossRefPubMed

28.

Prescott C, Weeks AM, Staley KJ, Partin KM (2006) Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett 402(1–2):108–112CrossRefPubMed

29.

Rozsa E, Robotka H, Vecsei L, Toldi J (2008) The Janus-face kynurenic acid. J Neural Transm (Vienna) 115(8):1087–1091CrossRef

30.

Kessler M, Terramani T, Lynch G, Baudry M (1989) A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem 52(4):1319–1328CrossRefPubMed

31.

Csati A, Edvinsson L, Vecsei L, Toldi J, Fulop F, Tajti J, Warfvinge K (2015) Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion. J Headache Pain 16:99CrossRefPubMedPubMedCentral

32.

Fejes-Szabo A, Bohar Z, Vamos E, Nagy-Grocz G, Tar L, Veres G, Zadori D, Szentirmai M, Tajti J, Szatmari I, Fulop F, Toldi J, Pardutz A, Vecsei L (2014) Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex. J Neural Transm (Vienna) 121(7):725–738CrossRef

33.

Knyihar-Csillik E, Toldi J, Mihaly A, Krisztin-Peva B, Chadaide Z, Nemeth H, Fenyo R, Vecsei L (2007) Kynurenine in combination with probenecid mitigates the stimulation-induced increase of c-fos immunoreactivity of the rat caudal trigeminal nucleus in an experimental migraine model. J Neural Transm (Vienna) 114(4):417–421CrossRef

34.

Knyihar-Csillik E, Toldi J, Krisztin-Peva B, Chadaide Z, Nemeth H, Fenyo R, Vecsei L (2007) Prevention of electrical stimulation-induced increase of c-fos immunoreaction in the caudal trigeminal nucleus by kynurenine combined with probenecid. Neurosci Lett 418(2):122–126CrossRefPubMed

35.

Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L (2010) Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169(2):683–696CrossRefPubMed

36.

Aminian O, Eftekhari S, Mazaheri M, Sharifian SA, Sadeghniiat-Haghighi K (2011) Urinary beta2 microglobulin in workers exposed to arc welding fumes. Acta Med Iran 49(11):748–752PubMed

37.

Kaiser EA, Russo AF (2013) CGRP and migraine: could PACAP play a role too? Neuropeptides 47(6):451–461CrossRefPubMed

38.

Helyes Z, Pozsgai G, Borzsei R, Nemeth J, Bagoly T, Mark L, Pinter E, Toth G, Elekes K, Szolcsanyi J, Reglodi D (2007) Inhibitory effect of PACAP-38 on acute neurogenic and non-neurogenic inflammatory processes in the rat. Peptides 28(9):1847–1855CrossRefPubMed

39.

Amin FM, Asghar MS, Guo S, Hougaard A, Hansen AE, Schytz HW, van der Geest RJ, de Koning PJ, Larsson HB, Olesen J, Ashina M (2012) Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia 32(2):140–149CrossRefPubMed

40.

Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsanyi J, Szabo N, Toth E, Kincses ZT, Vecsei L, Tajti J (2013) Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia 33(13):1085–1095CrossRefPubMed

41.

Tuka B, Szabo N, Toth E, Kincses ZT, Pardutz A, Szok D, Kortesi T, Bagoly T, Helyes Z, Edvinsson L, Vecsei L, Tajti J (2016) Release of PACAP-38 in episodic cluster headache patients - an exploratory study. J Headache Pain 17(1):69CrossRefPubMedPubMedCentral

42.

Mabuchi T, Shintani N, Matsumura S, Okuda-Ashitaka E, Hashimoto H, Muratani T, Minami T, Baba A, Ito S (2004) Pituitary adenylate cyclase-activating polypeptide is required for the development of spinal sensitization and induction of neuropathic pain. J Neurosci 24(33):7283–7291CrossRefPubMed

43.

Samsam M, Covenas R, Ahangari R, Yajeya J, Narvaez JA, Tramu G (2000) Simultaneous depletion of neurokinin A, substance P and calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat during electrical stimulation of the trigeminal ganglion. Pain 84(2–3):389–395CrossRefPubMed

44.

Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187CrossRefPubMed

45.

Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, Floridi A, Calabresi P (2006) Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 46(2):200–207CrossRefPubMed

46.

Perini F, D’Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V (2005) Plasma cytokine levels in migraineurs and controls. Headache 45(7):926–931CrossRefPubMed

Title: Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)
Authors: M. Lukács
K. Warfvinge
J. Tajti
F. Fülöp
J. Toldi
L. Vécsei
L. Edvinsson
Publication date: 01-12-2017
Publisher: Springer Milan
Published in: The Journal of Headache and Pain / Issue 1/2017
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-017-0746-x

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Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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