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

Journal of Pain Research Dovepress open access to scientific and medical research Original Research Journal of Pain Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 21-Dec-2018 For personal use only. Open Access Full Text Article Chronic 17β-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats This article was published in the following Dove Press journal: Journal of Pain Research 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 Párdutz 2 1 MTA-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; 4 Faculty 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 Introduction Correspondence: László Vécsei Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis Street 6, H-6725 Szeged, Hungary Tel +36 6 254 5351 Fax +36 6 254 5597 Email 2011 submit your manuscript | www.dovepress.com Journal of Pain Research 2018:11 2011–2021 Dovepress © 2018 Fejes-Szabó et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/JPR.S165969 Powered by TCPDF (www.tcpdf.org) The perception of intensity of pain or the responses to painkillers show differences between the sexes.1,2 Lower tolerance for pain, greater ability to discriminate painful sensations, lower pain thresholds and higher pain ratings can be observed in women.1–3 Moreover, the localization of pain according to body parts can amplify this sex-related difference, because this discrepancy is more pronounced in the case of craniofacial pain, which is usually more common in women. For example, temporomandibular disorders, mainly manifested in paroxysmal pain in the masticatory muscles and temporomandibular joints,4 are three times more prevalent in women.5 Also, more women than men Dovepress Journal of Pain Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 21-Dec-2018 For personal use only. Fejes-Szabó et al suffer from trigeminal neuralgia,6,7 which is characterized by recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli.8 Significant sex-related differences can be observed among the primary headache disorders as well. Women also have higher prevalence of tension-type headache than men,9 and migraine is three times more common in females compared to males.10 In contrast, cluster headache is five times more frequent in men than women.11 These data indicate that sex hormones may influence the development of trigeminal pain conditions, which is underlined by the observations, that migraine without aura usually starts after menarche, tends to be related to menstrual cycle and ameliorates during pregnancy and after menopause in women.12 In addition, the appearance of migraine without aura is thought to be related to the fall in estrogen concentrations prior to menstruation,12,13 while in migraine with aura an increase in attack frequency can be observed related to high estrogen levels, eg, pregnancy.14 Similarly, the marked female predominance appears only after puberty in the case of tension-type headache as well.15 Animal research data also show the presence of the sexual dimorphism and the modulatory effect of sex hormones on the orofacial pain;16 moreover, site-specific effect of sex hormones on nociception was detected in rats as well.17 These experimental data might give useful information concerning the molecular mechanisms underlying the sex differences in pain conditions, but they are rather controversial. Concerning the possible mechanisms, these sex-related differences in craniofacial pain disorders suggest that trigeminal neurons are sensitive to sex hormones, which can modulate their function. Hormonal receptors are present in both the trigeminal ganglion and the spinal trigeminal nucleus pars caudalis (TNC) providing the molecular basis for direct modulatory action on the peripheral and central sensitization in the trigeminal system.18–21 At present, however, t (...truncated)