Top

Published in:

Open Access 01-12-2022 | Migraine | Research article

Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model

Authors: Ruimin Tian, Yun Zhang, Qi Pan, Yunfeng Wang, Qianwen Wen, Xiaoping Fan, Guangcheng Qin, Dunke Zhang, Lixue Chen, Yixin Zhang, Jiying Zhou

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Background

Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN).

Methods

A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining.

Results

The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM.

Conclusions

The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.

Pan Q, Zhang Y, Long T et al (2018) Diagnosis of Vertigo and Dizziness Syndromes in a Neurological Outpatient Clinic. Eur Neurol 79:287–294. Doi https://doi.org/10.1159/000489639CrossRefPubMed

Carvalho GF, Vianna-Bell FH, Florencio LL et al (2019) Presence of vestibular symptoms and related disability in migraine with and without aura and chronic migraine. Cephalalgia: an international journal of headache 39:29–37. Doi https://doi.org/10.1177/0333102418769948CrossRef

Vuralli D, Yildirim F, Akcali DT et al (2018) Visual and Postural Motion-Evoked Dizziness Symptoms Are Predominant in Vestibular Migraine Patients. Pain Med 19:178–183. Doi https://doi.org/10.1093/pm/pnx182CrossRefPubMed

Huang TC, Wang SJ, Kheradmand A (2020) Vestibular migraine: An update on current understanding and future directions. Cephalalgia: an international journal of headache 40:107–121. Doi https://doi.org/10.1177/0333102419869317CrossRef

Goadsby PJ, Holland PR, Martins-Oliveira M et al (2017) Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev 97:553–622. Doi https://doi.org/10.1152/physrev.00034.2015CrossRefPubMedPubMedCentral

Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J pain 10:895–926. Doi https://doi.org/10.1016/j.jpain.2009.06.012CrossRefPubMedPubMedCentral

Su M, Yu S (2018) Chronic migraine: A process of dysmodulation and sensitization. Mol Pain 14:2070395823. Doi https://doi.org/10.1177/1744806918767697CrossRef

Zhang Y, Zhang Y, Tian K et al (2020) Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine. J Headache Pain 21:72. Doi https://doi.org/10.1186/s10194-020-01145-yCrossRefPubMedPubMedCentral

Ashina M, Hansen JM, Do TP et al (2019) Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol 18:795–804. Doi https://doi.org/10.1016/S1474-4422(19)30185-1CrossRefPubMedPubMedCentral

10.

Iyengar S, Ossipov MH, Johnson KW (2017) The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain 158:543–559. Doi https://doi.org/10.1097/j.pain.0000000000000831CrossRefPubMedPubMedCentral

11.

Russell FA, King R, Smillie SJ et al (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94:1099–1142. Doi https://doi.org/10.1152/physrev.00034.2013CrossRefPubMedPubMedCentral

12.

Walker CS, Conner AC, Poyner DR et al (2010) Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 31:476–483. Doi https://doi.org/10.1016/j.tips.2010.06.006CrossRefPubMed

13.

Xiaocheng W, Zhaohui S, Junhui X et al (2012) Expression of calcitonin gene-related peptide in efferent vestibular system and vestibular nucleus in rats with motion sickness. PLoS ONE 7:e47308. Doi https://doi.org/10.1371/journal.pone.0047308CrossRefPubMedPubMedCentral

14.

Charles A, Pozo-Rosich P (2019) Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet (London England) 394:1765–1774. Doi https://doi.org/10.1016/S0140-6736(19)32504-8CrossRef

15.

Liu Y, Chen QY, Lee JH et al (2020) Cortical potentiation induced by calcitonin gene-related peptide (CGRP) in the insular cortex of adult mice. Mol Brain 13:36. Doi https://doi.org/10.1186/s13041-020-00580-xCrossRefPubMedPubMedCentral

16.

Li XH, Matsuura T, Liu RH et al (2019) Calcitonin gene-related peptide potentiated the excitatory transmission and network propagation in the anterior cingulate cortex of adult mice. Mol Pain 15:2069330802. Doi https://doi.org/10.1177/1744806919832718CrossRef

17.

Han JS, Li W, Neugebauer V (2005) Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior. J neuroscience: official J Soc Neurosci 25:10717–10728. Doi https://doi.org/10.1523/JNEUROSCI.4112-05.2005CrossRef

18.

Cottrell GS (2019) CGRP Receptor Signalling Pathways. Handb Exp Pharmacol 255:37–64 Doi 10.1007/164_2018_130CrossRef

19.

Yarwood RE, Imlach WL, Lieu T et al (2017) Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission. P Natl Acad Sci Usa 114:12309–12314. Doi https://doi.org/10.1073/pnas.1706656114CrossRef

20.

Mitsikostas DD, Knight YE, Lasalandra M et al (2011) Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization? J Headache Pain 12:411–417. Doi https://doi.org/10.1007/s10194-011-0352-2CrossRefPubMedPubMedCentral

21.

Niu Y, Zeng X, Zhao L et al (2020) Metabotropic glutamate receptor 5 regulates synaptic plasticity in a chronic migraine rat model through the PKC/NR2B signal. J Headache Pain 21:139. Doi https://doi.org/10.1186/s10194-020-01206-2CrossRefPubMedPubMedCentral

22.

Long T, He W, Pan Q et al (2018) Microglia P2 × 4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation. J Neuroinflamm 15:245. Doi https://doi.org/10.1186/s12974-018-1285-3CrossRef

23.

Zeng X, Niu Y, Qin G et al (2020) Deficiency in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through GABABR2-SynCAM1 signaling in chronic migraine rats. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 34:14780–14798. Doi https://doi.org/10.1096/fj.202001561RCrossRef

24.

Wang Z, Ma W, Chabot JG et al (2010) Calcitonin gene-related peptide as a regulator of neuronal CaMKII-CREB, microglial p38-NFκB and astroglial ERK-Stat1/3 cascades mediating the development of tolerance to morphine-induced analgesia. Pain 151:194–205. Doi https://doi.org/10.1016/j.pain.2010.07.006CrossRefPubMed

25.

Zhou H, Wang X, Wang S et al (2019) Inhibition of Nerve Growth Factor Signaling Alleviates Repeated Dural Stimulation-induced Hyperalgesia in Rats. Neuroscience 398:252–262. Doi https://doi.org/10.1016/j.neuroscience.2018.12.006CrossRefPubMed

26.

Zhang J, Li B, Yu L et al (2011) A role for orexin in central vestibular motor control. Neuron 69:793–804. Doi https://doi.org/10.1016/j.neuron.2011.01.026CrossRefPubMed

27.

Motz BA, Alberts JR (2005) The validity and utility of geotaxis in young rodents. Neurotoxicol Teratol 27:529–533. Doi https://doi.org/10.1016/j.ntt.2005.06.005CrossRefPubMed

28.

Ramirez RL, Spear LP (2010) Ontogeny of ethanol-induced motor impairment following acute ethanol: assessment via the negative geotaxis reflex in adolescent and adult rats. Pharmacol Biochem Behav 95:242–248. Doi https://doi.org/10.1016/j.pbb.2010.01.013CrossRefPubMedPubMedCentral

29.

Zhou X, Liang J, Wang J et al (2020) Up-regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine. J Neurochem 155:370–389. Doi https://doi.org/10.1111/jnc.14944CrossRefPubMed

30.

Montardy Q, Wei M, Liu X et al (2021) Selective optogenetic stimulation of glutamatergic, but not GABAergic, vestibular nuclei neurons induces immediate and reversible postural imbalance in mice. Prog Neurobiol: 102085 Doi. https://doi.org/10.1016/j.pneurobio.2021.102085CrossRef

31.

Wang XY, Zhou HR, Wang S et al (2018) NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model. J Headache Pain 19:102. Doi https://doi.org/10.1186/s10194-018-0935-2CrossRefPubMedPubMedCentral

32.

Pradhan AA, Smith ML, McGuire B et al (2014) Characterization of a novel model of chronic migraine. Pain 155:269–274. Doi https://doi.org/10.1016/j.pain.2013.10.004CrossRefPubMed

33.

Edvinsson L (2017) The Trigeminovascular Pathway: Role of CGRP and CGRP Receptors in Migraine. Headache: 47–55 Doi https://doi.org/10.1111/head.13081

34.

Rollenhagen A, Lübke JH (2006) The morphology of excitatory central synapses: from structure to function. Cell Tissue Res 326:221–237. Doi https://doi.org/10.1007/s00441-006-0288-zCrossRefPubMed

35.

Jaworski J, Kapitein LC, Gouveia SM et al (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61:85–100. Doi https://doi.org/10.1016/j.neuron.2008.11.013CrossRefPubMed

36.

Harriott AM, Strother LC, Vila-Pueyo M et al (2019) Animal models of migraine and experimental techniques used to examine trigeminal sensory processing. J Headache Pain 20:91. Doi https://doi.org/10.1186/s10194-019-1043-7CrossRefPubMedPubMedCentral

37.

Iljazi A, Ashina H, Lipton RB et al (2020) Dizziness and vertigo during the prodromal phase and headache phase of migraine: A systematic review and meta-analysis. Cephalalgia: an international journal of headache 40:1095–1103. Doi https://doi.org/10.1177/0333102420921855CrossRefPubMed

38.

Li V, McArdle H, Trip SA (2019) Vestibular migraine. BMJ (Clinical research ed. 366:l4213. https://doi.org/10.1136/bmj.l4213

39.

Diagne M, Valla J, Delfini C et al (2006) Trigeminovestibular and trigeminospinal pathways in rats: retrograde tracing compared with glutamic acid decarboxylase and glutamate immunohistochemistry. J Comp Neurol 496:759–772. Doi https://doi.org/10.1002/cne.20964CrossRefPubMed

40.

Zhang Y, Kong Q, Chen J et al (2016) International Classification of Headache Disorders 3rd edition beta-based field testing of vestibular migraine in China: Demographic, clinical characteristics, audiometric findings and diagnosis statues. Cephalalgia: an international journal of headache 36:240–248. Doi https://doi.org/10.1177/0333102415587704CrossRef

41.

Radtke A, Neuhauser H, von Brevern M et al (2011) Vestibular migraine–validity of clinical diagnostic criteria. Cephalalgia: an international journal of headache 31:906–913. Doi https://doi.org/10.1177/0333102411405228CrossRef

42.

Brandes JL (2006) The influence of estrogen on migraine: a systematic review. JAMA 295:1824–1830. Doi https://doi.org/10.1001/jama.295.15.1824CrossRefPubMed

43.

Chai NC, Peterlin BL, Calhoun AH (2014) Migraine and estrogen. Curr Opin Neurol 27:315–324. Doi https://doi.org/10.1097/WCO.0000000000000091CrossRefPubMedPubMedCentral

44.

Craft RM (2007) Modulation of pain by estrogens. Pain: S3-S12 Doi https://doi.org/10.1016/j.pain.2007.09.028

45.

Silberstein SD (2000) Sex hormones and headache. 4S-30S, Rev Neurol-France

46.

Rybak LP (1995) Metabolic disorders of the vestibular system. Otolaryngology–head and neck surgery: official journal of American Academy of Otolaryngology-Head and Neck Surgery 112: 128–132 Doi https://doi.org/10.1016/S0194-59989570312-8

47.

Edvinsson L, Haanes KA, Warfvinge K et al (2018) CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat reviews Neurol 14:338–350. Doi https://doi.org/10.1038/s41582-018-0003-1CrossRef

48.

Garelja ML, Walker CS, Hay DL (2021) CGRP receptor antagonists for migraine. Are they also AMY receptor antagonists? Brit J Pharmacol Doi. https://doi.org/10.1111/bph.15585CrossRef

49.

Walker CS, Raddant AC, Woolley MJ et al (2018) CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia: an international journal of headache 38:437–451. Doi https://doi.org/10.1177/0333102417691762CrossRef

50.

Ghanizada H, Al-Karagholi MA, Arngrim N et al (2021) Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study. Neurology 96:e2488–e2499. Doi https://doi.org/10.1212/WNL.0000000000011930CrossRefPubMed

51.

Warfvinge K, Edvinsson L (2019) Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia: an international journal of headache 39:342–353. Doi https://doi.org/10.1177/0333102417728873CrossRefPubMed

52.

Campos CA, Bowen AJ, Roman CW et al (2018) Encoding of danger by parabrachial CGRP neurons. Nature 555:617–622. Doi https://doi.org/10.1038/nature25511CrossRefPubMedPubMedCentral

53.

Han JS, Adwanikar H, Li Z et al (2010) Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats. Mol Pain 6:10. Doi https://doi.org/10.1186/1744-8069-6-10CrossRefPubMedPubMedCentral

54.

Ehrlich I, Klein M, Rumpel S et al (2007) PSD-95 is required for activity-driven synapse stabilization. P Natl Acad Sci Usa 104:4176–4181. Doi https://doi.org/10.1073/pnas.0609307104CrossRef

55.

Thiel G (1993) Synapsin I, synapsin II, and synaptophysin: marker proteins of synaptic vesicles. Brain Pathol 3:87–95. Doi https://doi.org/10.1111/j.1750-3639.1993.tb00729.xCrossRefPubMed

56.

Valtorta F, Pennuto M, Bonanomi D et al (2004) Synaptophysin: leading actor or walk-on role in synaptic vesicle exocytosis? BioEssays: news and reviews in molecular, cellular and developmental biology. 26:445–453. https://doi.org/10.1002/bies.20012

57.

Bradberry MM, Courtney NA, Dominguez MJ et al (2020) Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder. Neuron 107:52–64. Doi https://doi.org/10.1016/j.neuron.2020.04.003CrossRefPubMedPubMedCentral

58.

Park Y, Ryu JK (2018) Models of synaptotagmin-1 to trigger Ca -dependent vesicle fusion. Febs Lett 592:3480–3492. Doi https://doi.org/10.1002/1873-3468.13193CrossRefPubMed

59.

Okutsu Y, Takahashi Y, Nagase M et al (2017) Potentiation of NMDA receptor-mediated synaptic transmission at the parabrachial-central amygdala synapses by CGRP in mice. Mol Pain 13:2071454319. Doi https://doi.org/10.1177/1744806917709201CrossRef

60.

Dickstein DL, Weaver CM, Luebke JI et al (2013) Dendritic spine changes associated with normal aging. Neuroscience 251:21–32. Doi https://doi.org/10.1016/j.neuroscience.2012.09.077CrossRefPubMed

61.

Hongpaisan J, Xu C, Sen A et al (2013) PKC activation during training restores mushroom spine synapses and memory in the aged rat. Neurobiol Dis 55:44–62. Doi https://doi.org/10.1016/j.nbd.2013.03.012CrossRefPubMed

62.

Sarajärvi T, Jäntti M, Paldanius K et al (2018) Protein kinase C -activating isophthalate derivatives mitigate Alzheimer’s disease-related cellular alterations. Neuropharmacology 141:76–88. Doi https://doi.org/10.1016/j.neuropharm.2018.08.020CrossRefPubMed

63.

Sun MK, Alkon DL (2014) The “memory kinases”: roles of PKC isoforms in signal processing and memory formation. Prog Mol Biol Transl 122:31–59. Doi 10.1016/B978-0-12-420170-5.00002-7

64.

Zhang H, Macara IG (2008) The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190 RhoGAP and the Rho GTPase. Dev Cell 14:216–226. Doi https://doi.org/10.1016/j.devcel.2007.11.020CrossRefPubMedPubMedCentral

Title: Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model
Authors: Ruimin Tian
Yun Zhang
Qi Pan
Yunfeng Wang
Qianwen Wen
Xiaoping Fan
Guangcheng Qin
Dunke Zhang
Lixue Chen
Yixin Zhang
Jiying Zhou
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Migraine
Nitroglycerin
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-022-01403-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Cerebral blood flow alterations in migraine patients with and without aura: An arterial spin labeling study

Correction: Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies

Correction to: Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats

Correction: Applying a biopsychosocial model to migraine: rationale and clinical implications

Assessment of peripheral biomarkers potentially involved in episodic and chronic migraine: a case-control study with a focus on NGF, BDNF, VEGF, and PGE2

Effects of eptinezumab on self-reported work productivity in adults with migraine and prior preventive treatment failure in the randomized, double-blind, placebo-controlled DELIVER study