Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2020

Open Access 01-12-2020 | Migraine | Research article

Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

Authors: Karin Warfvinge, Diana N. Krause, Aida Maddahi, Jacob C. A. Edvinsson, Lars Edvinsson, Kristian A. Haanes

Published in: The Journal of Headache and Pain | Issue 1/2020

Login to get access

Abstract

Background

Migraine occurs 2–3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes.

Methods

Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments.

Results

ERα was found throughout the whole brain, and in several migraine related structures. ERβ was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERβ which we observed only in female arteries.

Conclusion

These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.
Literature
1.
Katsarava Z, Mania M, Lampl C, Herberhold J, Steiner TJ (2018) Poor medical care for people with migraine in Europe - evidence from the Eurolight study. J Headache Pain 19(1):10PubMedPubMedCentralCrossRef
2.
Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB (2013) Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) study. Headache 53(8):1278–1299PubMedCrossRef
3.
MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A (2006) Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 67(12):2154–2158PubMedCrossRef
4.
Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72(5):381–405PubMedPubMedCentralCrossRef
5.
Carswell HV, Macrae IM, Farr TD (2009) Complexities of oestrogen in stroke. Clin Sci (Lond) 118(6):375–389CrossRef
6.
Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, McEwen BS, Warrier S, Alves SE (2005) Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. J Comp Neurol 491(2):81–95PubMedCrossRef
7.
Milner TA, McEwen BS, Hayashi S, Li CJ, Reagan LP, Alves SE (2001) Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol 429(3):355–371PubMedCrossRef
8.
Hammes SR, Levin ER (2007) Extranuclear steroid receptors: nature and actions. Endocr Rev 28(7):726–741PubMedCrossRef
9.
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307(5715):1625–1630PubMedCrossRef
10.
Zhang YY, Liu MY, Liu Z, Zhao JK, Zhao YG, He L, Li W, Zhang JQ (2019) GPR30-mediated estrogenic regulation of actin polymerization and spatial memory involves SRC-1 and PI3K-mTORC2 in the hippocampus of female mice. CNS Neurosci Ther 25(6):714–733PubMedPubMedCentralCrossRef
11.
Hart D, Nilges M, Pollard K, Lynn T, Patsos O, Shiel C, Clark SM, Vasudevan N (2014) Activation of the G-protein coupled receptor 30 (GPR30) has different effects on anxiety in male and female mice. Steroids 81:49–56PubMedCrossRef
12.
Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018) CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 14(6):338–350PubMedCrossRef
13.
Edvinsson JCA, Vigano A, Alekseeva A, Alieva E, Arruda R, De Luca C, D'Ettore N, Frattale I, Kurnukhina M, Macerola N et al (2020) The fifth cranial nerve in headaches. J Headache Pain 21(1):65PubMedPubMedCentralCrossRef
14.
Charles A, Pozo-Rosich P (2019) Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 394(10210):1765–1774PubMedCrossRef
15.
Haanes KA, Edvinsson L (2019) Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs
16.
Kitazawa T, Hamada E, Kitazawa K, Gaznabi AK (1997) Non-genomic mechanism of 17 beta-oestradiol-induced inhibition of contraction in mammalian vascular smooth muscle. J Physiol 499(Pt 2):497–511PubMedPubMedCentralCrossRef
17.
Chrissobolis S, Budzyn K, Marley PD, Sobey CG (2004) Evidence that estrogen suppresses rho-kinase function in the cerebral circulation in vivo. Stroke 35(9):2200–2205PubMedCrossRef
18.
McNeill AM, Zhang C, Stanczyk FZ, Duckles SP, Krause DN (2002) Estrogen increases endothelial nitric oxide synthase via estrogen receptors in rat cerebral blood vessels: effect preserved after concurrent treatment with medroxyprogesterone acetate or progesterone. Stroke 33(6):1685–1691PubMedCrossRef
19.
Pavlovic JM, Allshouse AA, Santoro NF, Crawford SL, Thurston RC, Neal-Perry GS, Lipton RB, Derby CA (2016) Sex hormones in women with and without migraine: evidence of migraine-specific hormone profiles. Neurology 87(1):49–56PubMedPubMedCentralCrossRef
20.
Somerville BW (1972) The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22(4):355–365PubMedCrossRef
21.
Gupta S, McCarson KE, Welch KM, Berman NE (2011) Mechanisms of pain modulation by sex hormones in migraine. Headache 51(6):905–922PubMedCrossRef
22.
Warfvinge K, Krause DN, Maddahi A, Grell AS, Edvinsson JC, Haanes KA, Edvinsson L (2020) Oxytocin as a regulatory neuropeptide in the trigeminovascular system: localization, expression and function of oxytocin and oxytocin receptors. Cephalalgia 333102420929027
23.
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, London
24.
Warfvinge K, Edvinsson L (2019) Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia 39(3):342–353PubMedCrossRef
25.
Forbes DJ, Welt C (1981) Neurogenesis in the trigeminal ganglion of the albino rat: a quantitative autoradiographic study. J Comp Neurol 199(1):133–147PubMedCrossRef
26.
Edvinsson JCA, Grell AS, Warfvinge K, Sheykhzade M, Edvinsson L, Haanes KA (2020) Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system. Cephalalgia 333102420929026
27.
Haanes KA, Labastida-Ramirez A, Blixt FW, Rubio-Beltran E, Dirven CM, Danser AH, Edvinsson L, MaassenVanDenBrink A (2019) Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models. Cephalalgia 39(11):1421–1434PubMedCrossRef
28.
Bryan RM Jr, Eichler MY, Swafford MW, Johnson TD, Suresh MS, Childres WF (1996) Stimulation of alpha 2 adrenoceptors dilates the rat middle cerebral artery. Anesthesiology 85(1):82–90PubMedCrossRef
29.
Grande G, Nilsson E, Edvinsson L (2013) Comparison of responses to vasoactive drugs in human and rat cerebral arteries using myography and pressurized cerebral artery method. Cephalalgia 33(3):152–159PubMedCrossRef
30.
Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41(1):19–26PubMedCrossRef
31.
Grande G, Labruijere S, Haanes KA, MaassenVanDenBrink A, Edvinsson L (2014) Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds. J Headache Pain 15:22PubMedPubMedCentralCrossRef
32.
Ohlsson L, Haanes KA, Kronvall E, Xu C, Snellman J, Edvinsson L (2019) Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries. Cephalalgia 39(14):1745–1752PubMedCrossRef
33.
Edvinsson JCA, Warfvinge K, Krause DN, Blixt FW, Sheykhzade M, Edvinsson L, Haanes KA (2019) C-fibers may modulate adjacent Adelta-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain 20(1):105PubMedPubMedCentralCrossRef
34.
Petersen KA, Nilsson E, Olesen J, Edvinsson L (2005) Presence and function of the calcitonin gene-related peptide receptor on rat pial arteries investigated in vitro and in vivo. Cephalalgia 25(6):424–432PubMedCrossRef
35.
Patkar S, Farr TD, Cooper E, Dowell FJ, Carswell HV (2011) Differential vasoactive effects of oestrogen, oestrogen receptor agonists and selective oestrogen receptor modulators in rat middle cerebral artery. Neurosci Res 71(1):78–84PubMedCrossRef
36.
Malmsjo M, Edvinsson L, Erlinge D (1998) P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation. Br J Pharmacol 123(4):719–729PubMedPubMedCentralCrossRef
37.
Wihlborg AK, Malmsjo M, Eyjolfsson A, Gustafsson R, Jacobson K, Erlinge D (2003) Extracellular nucleotides induce vasodilatation in human arteries via prostaglandins, nitric oxide and endothelium-derived hyperpolarising factor. Br J Pharmacol 138(8):1451–1458PubMedPubMedCentralCrossRef
38.
Saito K, Cui H (2018) Emerging Roles of Estrogen-Related Receptors in the Brain: Potential Interactions with Estrogen Signaling. Int J Mol Sci:19(4)
39.
Rossetti MF, Cambiasso MJ, Holschbach MA, Cabrera R (2016) Oestrogens and Progestagens: Synthesis and Action in the Brain. J Neuroendocrinol:28(7)
40.
Martin VT, Behbehani M (2006) Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part 2. Headache 46(3):365–386PubMedCrossRef
41.
Couturier EG, Bomhof MA, Neven AK, van Duijn NP (2003) Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia 23(4):302–308PubMedCrossRef
42.
43.
Gupta S, Mehrotra S, Villalon CM, Perusquia M, Saxena PR, MaassenVanDenBrink A (2007) Potential role of female sex hormones in the pathophysiology of migraine. Pharmacol Ther 113(2):321–340PubMedCrossRef
44.
MacGregor EA, Chia H, Vohrah RC, Wilkinson M (1990) Migraine and menstruation: a pilot study. Cephalalgia 10(6):305–310PubMedCrossRef
45.
Maasumi K, Tepper SJ, Kriegler JS (2017) Menstrual migraine and treatment options: review. Headache 57(2):194–208PubMedCrossRef
46.
Wang D, Zhao J, Wang J, Li J, Yu S, Guo X (2014) Deficiency of female sex hormones augments PGE2 and CGRP levels within midbrain periaqueductal gray. J Neurol Sci 346(1–2):107–111PubMedCrossRef
47.
Cetinkaya A, Kilinc E, Camsari C, Ogun MN (2020) Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine. Exp Brain Res 238(11):2625–2639PubMedCrossRef
48.
Aloisi AM (2003) Gonadal hormones and sex differences in pain reactivity. Clin J Pain 19(3):168–174PubMedCrossRef
49.
May A (2017) Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci 38(Suppl 1):125–130PubMedCrossRef
50.
Craft RM (2007) Modulation of pain by estrogens. Pain 132(Suppl 1):S3-12PubMed
51.
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd (2009) Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 10(5):447–485PubMedPubMedCentralCrossRef
52.
McNeill AM, Duckles SP, Krause DN (1996) Relaxant effects of 17 beta-estradiol in the rat tail artery are greater in females than males. Eur J Pharmacol 308(3):305–309PubMedCrossRef
Metadata
Title
Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects
Authors
Karin Warfvinge
Diana N. Krause
Aida Maddahi
Jacob C. A. Edvinsson
Lars Edvinsson
Kristian A. Haanes
Publication date
01-12-2020
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2020
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-020-01197-0

Other articles of this Issue 1/2020

The Journal of Headache and Pain 1/2020 Go to the issue

Research article

Disrupted functional connectivity between sub-regions in the sensorimotor areas and cortex in migraine without aura

Research article

Validation of an algorithm for automated classification of migraine and tension-type headache attacks in an electronic headache diary

Short report

Neuropeptide FF receptor 2 inhibits capsaicin-induced CGRP Upregulation in mouse trigeminal ganglion

Research article

Migraine, headache, and mortality in women: a cohort study

Review article

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence

Editorial

Two decades, a new editorial stylistic feature