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Chronic 17β-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats

Authors Fejes-Szabó A, Spekker E, Tar L, Nagy-Grócz G, Bohár Z, Laborc KF, Vécsei L, Párdutz A

Received 11 March 2018

Accepted for publication 18 June 2018

Published 25 September 2018 Volume 2018:11 Pages 2011—2021

DOI https://doi.org/10.2147/JPR.S165969

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Erica Wegrzyn


Annamária Fejes-Szabó,1 Eleonóra Spekker,2 Lilla Tar,3 Gábor Nagy-Grócz,1,4 Zsuzsanna Bohár,1,2 Klaudia Flóra Laborc,2,5 László Vécsei,1,2 Árpád Párdutz2

1MTA-SZTE Neuroscience Research Group, Szeged, Hungary; 2Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary; 3Department of Neurology, University of Ulm, Ulm, Germany; 4Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary; 5Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

Background: The prevalence of craniofacial pain disorders show sexual dimorphism with generally more common appearance in women suggesting the influence of estradiol, but the exact cause remains unknown. The common point in the pathogenesis of these disorders is the activation of trigeminal system. One of the animal experimental models of trigeminal activation is the orofacial formalin test, in which we investigated the effect of chronic 17β-estradiol pretreatment on the trigeminal pain-related behavior and activation of trigeminal second-order neurons at the level of spinal trigeminal nucleus pars caudalis (TNC).
Methods: Female Sprague Dawley rats were ovariectomized and silicone capsules were implanted subcutaneously containing cholesterol in the OVX group and 17β-estradiol and cholesterol in 1:1 ratio in the OVX+E2 group. We determined 17β-estradiol levels in serum after the implantation of capsules. Three weeks after operation, 50 µL of physiological saline or 1.5% of formalin solution was injected subcutaneously into the right whisker pad of rats. The time spent on rubbing directed to the injected area and c-Fos immunoreactivity in TNC was measured as the formalin-induced pain-related behavior, and as the marker of pain-related neuronal activation, respectively.
Results: The chronic 17β-estradiol pretreatment mimics the plasma levels of estrogen occurring in the proestrus phase and significantly increased the formalin-induced pain-related behavior and neuronal activation in TNC.
Conclusion: Our results demonstrate that the chronic 17β-estradiol treatment has strong ­pronociceptive effect on orofacial formalin-induced inflammatory pain suggesting modulatory action of estradiol on head pain through estrogen receptors, which are present in the trigeminal system.

Keywords: c-Fos, headache, pain, sexual dimorphism, trigeminal system

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