Cargando…

Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine

A migraine is a neurological condition that can cause multiple symptoms. It is up to three times more common in women than men, thus, estrogen may play an important role in the appearance attacks. Its exact pathomechanism is still unknown; however, the activation and sensitization of the trigeminal...

Descripción completa

Detalles Bibliográficos
Autores principales: Spekker, Eleonóra, Bohár, Zsuzsanna, Fejes-Szabó, Annamária, Szűcs, Mónika, Vécsei, László, Párdutz, Árpád
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776064/
https://www.ncbi.nlm.nih.gov/pubmed/36551931
http://dx.doi.org/10.3390/biomedicines10123175
_version_ 1784855786391863296
author Spekker, Eleonóra
Bohár, Zsuzsanna
Fejes-Szabó, Annamária
Szűcs, Mónika
Vécsei, László
Párdutz, Árpád
author_facet Spekker, Eleonóra
Bohár, Zsuzsanna
Fejes-Szabó, Annamária
Szűcs, Mónika
Vécsei, László
Párdutz, Árpád
author_sort Spekker, Eleonóra
collection PubMed
description A migraine is a neurological condition that can cause multiple symptoms. It is up to three times more common in women than men, thus, estrogen may play an important role in the appearance attacks. Its exact pathomechanism is still unknown; however, the activation and sensitization of the trigeminal system play an essential role. We aimed to use an animal model, which would better illustrate the process of repeated episodic migraine attacks to reveal possible new mechanisms of trigeminal pain chronification. Twenty male (M) and forty ovariectomized (OVX) female adult rats were used for our experiment. Male rats were divided into two groups (M + SIF, M + IS), while female rats were divided into four groups (OVX + SIF, OVX + IS, OVX + E2 + SIF, OVX + E2 + IS); half of the female rats received capsules filled with cholesterol (OVX + SIF, OVX + IS), while the other half received a 1:1 mixture of cholesterol and 17β-estradiol (OVX + E2 + SIF, OVX + E2 + IS). The animals received synthetic interstitial fluid (SIF) (M + SIF, OVX + SIF, OVX + E2 + SIF) or inflammatory soup (IS) (M + IS, OVX + IS, OVX + E2 + IS) treatment on the dural surface through a cannula for three consecutive days each week (12 times in total). Behavior tests and immunostainings were performed. After IS application, a significant decrease was observed in the pain threshold in the M + IS (0.001 < p < 0.5), OVX + IS (0.01 < p < 0.05), and OVX + E2 + IS (0.001 < p < 0.05) groups compared to the control groups (M + SIF; OVX + SIF, OVX + E2 + SIF). The locomotor activity of the rats was lower in the IS treated groups (M + IS, 0.01 < p < 0.05; OVX + IS, p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05), and these animals spent more time in the dark room (M + IS, p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.01). We found a significant difference between M + IS and OVX + E2 + IS groups (p < 0.05) in the behavior tests. Furthermore, IS increased the area covered by calcitonin gene-related peptide (CGRP) immunoreactive (IR) fibers (M + IS, p < 0.01; OVX + IS, p < 0.01; OVX + E2 + IS, p < 0.001) and the number of neuronal nitric oxide synthase (nNOS) IR cells (M + IS, 0.001< p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05) in the caudal trigeminal nucleus (TNC). There was no difference between M + IS and OVX + IS groups; however, the area was covered by CGRP IR fibers (0.01 < p < 0.05) and the number of nNOS IR cells was significantly higher in the OVX + E2 + IS (p < 0.05) group than the other two IS- (M + IS, OVX + IS) treated animals. Overall, repeated administration of IS triggers activation and sensitization processes and develops nociceptive behavior changes. CGRP and nNOS levels increased significantly in the TNC after IS treatments, and moreover, pain thresholds and locomotor activity decreased with the development of photophobia. In our model, stable high estradiol levels proved to be pronociceptive. Thus, repeated trigeminal activation causes marked behavioral changes, which is more prominent in rats treated with estradiol, also reflected by the expression of the sensitization markers of the trigeminal system.
format Online
Article
Text
id pubmed-9776064
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97760642022-12-23 Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine Spekker, Eleonóra Bohár, Zsuzsanna Fejes-Szabó, Annamária Szűcs, Mónika Vécsei, László Párdutz, Árpád Biomedicines Article A migraine is a neurological condition that can cause multiple symptoms. It is up to three times more common in women than men, thus, estrogen may play an important role in the appearance attacks. Its exact pathomechanism is still unknown; however, the activation and sensitization of the trigeminal system play an essential role. We aimed to use an animal model, which would better illustrate the process of repeated episodic migraine attacks to reveal possible new mechanisms of trigeminal pain chronification. Twenty male (M) and forty ovariectomized (OVX) female adult rats were used for our experiment. Male rats were divided into two groups (M + SIF, M + IS), while female rats were divided into four groups (OVX + SIF, OVX + IS, OVX + E2 + SIF, OVX + E2 + IS); half of the female rats received capsules filled with cholesterol (OVX + SIF, OVX + IS), while the other half received a 1:1 mixture of cholesterol and 17β-estradiol (OVX + E2 + SIF, OVX + E2 + IS). The animals received synthetic interstitial fluid (SIF) (M + SIF, OVX + SIF, OVX + E2 + SIF) or inflammatory soup (IS) (M + IS, OVX + IS, OVX + E2 + IS) treatment on the dural surface through a cannula for three consecutive days each week (12 times in total). Behavior tests and immunostainings were performed. After IS application, a significant decrease was observed in the pain threshold in the M + IS (0.001 < p < 0.5), OVX + IS (0.01 < p < 0.05), and OVX + E2 + IS (0.001 < p < 0.05) groups compared to the control groups (M + SIF; OVX + SIF, OVX + E2 + SIF). The locomotor activity of the rats was lower in the IS treated groups (M + IS, 0.01 < p < 0.05; OVX + IS, p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05), and these animals spent more time in the dark room (M + IS, p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.01). We found a significant difference between M + IS and OVX + E2 + IS groups (p < 0.05) in the behavior tests. Furthermore, IS increased the area covered by calcitonin gene-related peptide (CGRP) immunoreactive (IR) fibers (M + IS, p < 0.01; OVX + IS, p < 0.01; OVX + E2 + IS, p < 0.001) and the number of neuronal nitric oxide synthase (nNOS) IR cells (M + IS, 0.001< p < 0.05; OVX + IS, 0.01 < p < 0.05; OVX + E2 + IS, 0.001 < p < 0.05) in the caudal trigeminal nucleus (TNC). There was no difference between M + IS and OVX + IS groups; however, the area was covered by CGRP IR fibers (0.01 < p < 0.05) and the number of nNOS IR cells was significantly higher in the OVX + E2 + IS (p < 0.05) group than the other two IS- (M + IS, OVX + IS) treated animals. Overall, repeated administration of IS triggers activation and sensitization processes and develops nociceptive behavior changes. CGRP and nNOS levels increased significantly in the TNC after IS treatments, and moreover, pain thresholds and locomotor activity decreased with the development of photophobia. In our model, stable high estradiol levels proved to be pronociceptive. Thus, repeated trigeminal activation causes marked behavioral changes, which is more prominent in rats treated with estradiol, also reflected by the expression of the sensitization markers of the trigeminal system. MDPI 2022-12-08 /pmc/articles/PMC9776064/ /pubmed/36551931 http://dx.doi.org/10.3390/biomedicines10123175 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Spekker, Eleonóra
Bohár, Zsuzsanna
Fejes-Szabó, Annamária
Szűcs, Mónika
Vécsei, László
Párdutz, Árpád
Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title_full Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title_fullStr Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title_full_unstemmed Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title_short Estradiol Treatment Enhances Behavioral and Molecular Changes Induced by Repetitive Trigeminal Activation in a Rat Model of Migraine
title_sort estradiol treatment enhances behavioral and molecular changes induced by repetitive trigeminal activation in a rat model of migraine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776064/
https://www.ncbi.nlm.nih.gov/pubmed/36551931
http://dx.doi.org/10.3390/biomedicines10123175
work_keys_str_mv AT spekkereleonora estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine
AT boharzsuzsanna estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine
AT fejesszaboannamaria estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine
AT szucsmonika estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine
AT vecseilaszlo estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine
AT pardutzarpad estradioltreatmentenhancesbehavioralandmolecularchangesinducedbyrepetitivetrigeminalactivationinaratmodelofmigraine