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Evaluation of cooperative mechanisms between opioidergic and serotonergic systems in the dorsal periaqueductal grey matter in the antidepressants effects

Grant number: 12/23238-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2013
Effective date (End): August 31, 2015
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Norberto Cysne Coimbra
Grantee:Camila Marroni Roncon
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Fluoxetine, a reuptake serotonin inhibitor, has been used in the treatment of panic disorder as a first choice drug. However, there are some limitations for the use of fluoxetine, considering the time-window for its first clinical effect and anxiety-like effect commonly observed after the first days of treatment in patients diagnosed with panic syndrome. The dorsal periaqueductal grey matter (dPAG), considered as a key mesencephalic structure involved in the organisation of fear- and anxiety-related defensive responses is rich in both serotonergic and opioid receptors. Alterations in opioid and serotonergic signaling pathways have been recently reported in experimental models of panic attacks. Evidence suggest that the facilitation of serotonergic neurotransmission in the dPAG is involved in therapeutic effect of Medicines used for the treatment of panic syndrome. This is more specifically reported for the antipanic-like effect of fluoxetine that seems to be mediated by endogenous opioid peptides. Psychopharmacological studies show that the interaction between serotonin and opioid peptides is done through 5-HT1A and µ-opioid receptors into the dPAG. However, the morphological bases of that interaction were not demonstrated yet, although there is evidence showing beta-endorpihn-labelled fibres and perikarya in dPAG. It is important the study and development of new therapeutic strategies for the treatment of mental disorders, considering that there is a significant latency for the clinical effect of antidepressants. This phenomenon seems to be related to sensitization of 5-HT1A and 5HT2A serotonergic receptors. There is evidence that varicose fibres, a morphlogical charachteristic of monoaminergic pathways, can be also positive to beta-endorphin, neurotransmitters with high affinity for µ-opioid receptors. Considering these evidence, the aim of the present work is to investigate the effect of the pre-treatment of the dPAG with the m-opioid receptor agonist DAMGO of Wistar rats chronically treated with with fluoxetine.In addition, we will verify the presence of co-localization of endogenous opioid petides and serotonin in varicose fibres and interneurons of the dPAG. Finally, aiming at the localization 5-HT1A serotonergic and m-opioid receptors on pre- and post-synaptic membranes of synaptic contacts in the dorsal aspects of the periaqueductal grey matter, imunohistochemical reactions will also be ultrastructurally performed, using Laser microdissecation techniques (PALM MibroBeam; Zeiss) and transmission microscopy. (AU)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CALVO, FABRICIO; ALMADA, RAFAEL CARVALHO; DA SILVA, JULIANA ALMEIDA; MEDEIROS, PRISCILA; SOARES, JR., RAIMUNDO DA SILVA; DE PAIVA, YARA BEZERRA; RONCON, CAMILA MARRONI; COIMBRA, NORBERTO CYSNE. The Blockade of mu(1)- and kappa-Opioid Receptors in the Inferior Colliculus Decreases the Expression of Panic Attack-Like Behaviours Induced by Chemical Stimulation of the Dorsal Midbrain. NEUROPSYCHOBIOLOGY, v. 78, n. 4, p. 218-228, NOV 2019. Web of Science Citations: 0.
MARASCHINA, JHONATAN CHRISTIAN; ALMEIDA, CAMILA BIESDORF; RANGEL, MARCEL PEREIRA; RONCON, CAMILA MARRONI; SESTILE, CAIO CESAR; ZANGROSSI, JR., HELIO; GRAEFF, FREDERICO GUILHERME; AUDI, ELISABETH APARECIDA. Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the kappa-opioid receptor antagonist Nor-BNI. Behavioural Brain Research, v. 327, p. 75-82, JUN 1 2017. Web of Science Citations: 3.
RONCON, CAMILA MARRONI; DE MELO YAMASHITA, PAULA SHIMENE; FRIAS, ALANA TERCINO; AUDI, ELISABETH APARECIDA; GRAEFF, FREDERICO GUILHERME; COIMBRA, NORBERTO CYSNE; ZANGROSSI, HELIO. mu-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses. JOURNAL OF PSYCHOPHARMACOLOGY, v. 31, n. 6, p. 715-721, JUN 2017. Web of Science Citations: 3.
BIAGIONI, AUDREY FRANCESCHI; DE OLIVEIRA, RITHIELE CRISTINA; DE OLIVEIRA, RICARDO; DA SILVA, JULIANA ALMEIDA; DOS ANJOS-GARCIA, TAYLION; RONCON, CAMILA MARRONI; CORRADO, ALEXANDRE PINTO; ZANGROSSI, JR., HELIO; COIMBRA, NORBERTO CYSNE. 5-Hydroxytryptamine(1A) receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception. European Neuropsychopharmacology, v. 26, n. 3, p. 532-545, MAR 2016. Web of Science Citations: 17.
RONCON, CAMILA MARRONI; ALMADA, RAFAEL CARVALHO; MARASCHIN, JHONATAN CHRISTIAN; AUDI, ELISABETH APARECIDA; ZANGROSSI, JR., HELIO; GRAEFF, FREDERICO GUILHERME; COIMBRA, NORBERTO CYSNE. Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter mu-opioid receptors. Neuropharmacology, v. 99, p. 620-626, DEC 2015. Web of Science Citations: 15.
ALMADA, R. C.; RONCON, C. M.; ELIAS-FILHO, D. H.; COIMBRA, N. C. ENDOCANNABINOID SIGNALING MECHANISMS IN THE SUBSTANTIA NIGRA PARS RETICULATA MODULATE GABAergic NIGROTECTAL PATHWAYS IN MICE THREATENED BY URUTU-CRUZEIRO VENOMOUS PIT VIPER. Neuroscience, v. 303, p. 503-514, SEP 10 2015. Web of Science Citations: 19.

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