Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine

Dong,Xiaomeng; Hu,Yaozhi; Jing,Long; Chen,Jinbo

doi:10.3892/mmr.2015.3616

Role of phosphorylated extracellular signal-regulated kinase, calcitonin gene-related peptide and cyclooxygenase-2 in experimental rat models of migraine

Authors:
- Xiaomeng Dong
- Yaozhi Hu
- Long Jing
- Jinbo Chen
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Affiliations: Binzhou Medical University, Yantai, Shandong 264003, P.R. China, Department of Special Inspection, Binzhou People's Hospital, Binzhou, Shandong 256610, P.R. China, Department of Neurology, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
Published online on: April 15, 2015 https://doi.org/10.3892/mmr.2015.3616
Pages: 1803-1809
Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Although migraine is a common neurological condition, the pathomechanism is not yet fully understood. Activation of the trigeminovascular system (TVS) has an important function in this disorder and neurogenic inflammation and central sensitization are important mechanisms underlying this condition. Nitroglycerin (NTG) infusion in rats closely mimics a universally accepted human model of migraine. Electrical stimulation of the trigeminal ganglion (ESTG) of rats can also activate TVS during a migraine attack. Numerous studies have revealed that phosphorylated extracellular signal‑regulated kinase (p‑ERK), calcitonin gene‑related peptide (CGRP) and cyclooxygenase‑2 (COX‑2) are involved in pain and nociceptive pathways. However, few studies have examined whether p‑ERK, CGRP and COX‑2 are involved in neurogenic inflammation and central sensitization. In the present study, the expression of p‑ERK, CGRP and COX‑2 was detected in the dura mater, trigeminal ganglion (TG) and spinal trigeminal nucleus caudalis in NTG‑induced rats and ESTG models by immunohistochemistry. The three areas considered were crucial components of the TVS. The selective COX‑2 inhibitor nimesulide was used in ESTG rats to examine the association between p‑ERK, CGRP and COX‑2. The results demonstrated that p‑ERK, CGRP and COX‑2 mediated neurogenic inflammation and central sensitization in migraine. In addition, the expression of p‑ERK and CGRP was attenuated by the COX-2 inhibitor.

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1	Noseda R and Burstein R: Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization and modulation of pain. Pain. 154(Suppl 1): S44–S53. 2013. View Article : Google Scholar
2	Kojić Z and Stojanović D: Pathophysiology of migraine - from molecular to personalized medicine. Med Pregl. 66:53–57. 2013. View Article : Google Scholar
3	Goadsby PJ: Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med. 13:39–44. 2007. View Article : Google Scholar
4	Knyihar-Csillik E, Tajti J, Mohtasham S, Sari G and Vecsei L: Electrical stimulation of the Gasserian ganglion induces structural alterations of calcitonin gene-related peptide-immunoreactive perivascular sensory nerve terminals in the rat cerebral dura mater: a possible model of migraine headache. Neurosci Lett. 184:189–192. 1995. View Article : Google Scholar : PubMed/NCBI
5	Louter MA, Bosker JE, van Oosterhout WP, et al: Cutaneous allodynia as a predictor of migraine chronification. Brain. 136:3489–3496. 2013. View Article : Google Scholar : PubMed/NCBI
6	Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ and Bajwa ZH: An association between migraine and cutaneous allodynia. Ann Neurol. 47:614–624. 2000. View Article : Google Scholar : PubMed/NCBI
7	Lovati C, Mariotti C, Giani L, et al: Central sensitization in photophobic and non-photophobic migraineurs: possible role of retino nuclear way in the central sensitization process. Neurol Sci. 34(Suppl 1): S133–S135. 2013. View Article : Google Scholar : PubMed/NCBI
8	Roux PP and Blenis J: ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 68:320–344. 2004. View Article : Google Scholar : PubMed/NCBI
9	Shimizu K, Asano M, Kitagawa J, et al: Phosphorylation of extracellular signal-regulated kinase in medullary and upper cervical cord neurons following noxious tooth pulp stimulation. Brain Res. 1072:99–109. 2006. View Article : Google Scholar : PubMed/NCBI
10	Zhang X, Kainz V, Zhao J, Strassman AM and Levy D: Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol. 73:741–750. 2013. View Article : Google Scholar : PubMed/NCBI
11	Iwashita T, Shimizu T, Shibata M, et al: Activation of extracellular signal-regulated kinase in the trigeminal ganglion following both treatment of the dura mater with capsaicin and cortical spreading depression. Neurosci Res. 77:110–119. 2013. View Article : Google Scholar : PubMed/NCBI
12	Durham PL: Calcitonin gene-related peptide (CGRP) and migraine. Headache. 46(Suppl 1): S3–S8. 2006. View Article : Google Scholar : PubMed/NCBI
13	Kim GM, Jin KS and Chung CS: Differential effects of corticosteroids on the expression of cyclooxygenase-2, tumour necrosis factor-alpha and matrix metalloproteinase-9 in an animal model of migraine. Cephalalgia. 28:1179–1187. 2008. View Article : Google Scholar : PubMed/NCBI
14	Waeber C and Moskowitz MA: Migraine as an inflammatory disorder. Neurology. 64(Suppl 2): S9–S15. 2005. View Article : Google Scholar : PubMed/NCBI
15	Storer RJ, Akerman S and Goadsby PJ: Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol. 142:1171–1181. 2004. View Article : Google Scholar : PubMed/NCBI
16	Neeb L, Hellen P, Boehnke C, et al: IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells. PLoS one. 6:e173602011. View Article : Google Scholar
17	Kawabata A: Prostaglandin E2 and pain - an update. Biol Pharm Bull. 34:1170–1173. 2011. View Article : Google Scholar
18	Tassorelli C, Greco R, Armentero MT, Blandini F, Sandrini G and Nappi G: A role for brain cyclooxygenase-2 and prostaglandin-E2 in migraine: effects of nitroglycerin. Int Rev Neurobiol. 82:373–382. 2007.PubMed/NCBI
19	Varga H, Pardutz A, Vamos E, et al: Cox-2 inhibitor attenuates NO-induced nNOS in rat caudal trigeminal nucleus. Headache. 47:1319–1325. 2007. View Article : Google Scholar : PubMed/NCBI
20	Iversen HK, Olesen J and Tfelt-Hansen P: Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain. 38:17–24. 1989. View Article : Google Scholar : PubMed/NCBI
21	Tassorelli C and Joseph SA: Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res. 682:167–181. 1995. View Article : Google Scholar : PubMed/NCBI
22	Tassorelli C, Greco R, Wang D, Sandrini M, Sandrini G and Nappi G: Nitroglycerin induces hyperalgesia in rats - a time-course study. Eur J Pharmacol. 464:159–162. 2003. View Article : Google Scholar : PubMed/NCBI
23	Kaiser EA and Russo AF: CGRP and migraine: Could PACAP play a role too? Neuropeptides. 47:451–461. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ramachandran R, Bhatt DK, Ploug KB, et al: Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia. 34:136–147. 2014. View Article : Google Scholar
25	Aguggia M, Saracco M, Cavallini M, Bussone G and Cortelli P: Sensitization and pain. Neurol Sci. 34(Suppl 1): S37–S40. 2013. View Article : Google Scholar : PubMed/NCBI
26	Silberstein SD: Migraine pathophysiology and its clinical implications. Cephalalgia. 24(Suppl 2): 2–7. 2004. View Article : Google Scholar : PubMed/NCBI
27	Arulmani U, Gupta S, VanDenBrink AM, Centurión D, Villalón C and Saxena P: Experimental migraine models and their relevance in migraine therapy. Cephalalgia. 26:642–659. 2006. View Article : Google Scholar : PubMed/NCBI
28	Varga H, Pardutz A, Vamos E, et al: Selective inhibition of cyclooxygenase-2 attenuates nitroglycerin-induced calmodulin-dependent protein kinase II alpha in rat trigeminal nucleus caudalis. Neurosci Lett. 451:170–173. 2009. View Article : Google Scholar : PubMed/NCBI
29	Tassorelli C, Greco R, Morazzoni P, Riva A, Sandrini G and Nappi G: Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine. Cephalalgia. 25:612–621. 2005. View Article : Google Scholar : PubMed/NCBI
30	Dai Y, Iwata K, Fukuoka T, et al: Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci. 22:7737–7745. 2002.PubMed/NCBI
31	Levy D, Burstein R, Kainz V, Jakubowski M and Strassman AM: Mast cell degranulation activates a pain pathway underlying migraine headache. Pain. 130:166–176. 2007. View Article : Google Scholar : PubMed/NCBI
32	Obata K and Noguchi K: MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 74:2643–2653. 2004. View Article : Google Scholar : PubMed/NCBI