Role of bradykinin B2 receptors in the modulation of defensive reactions related to panic: intracellular signalling pathways involved and interaction with µ-opioid receptor

• Grant number: 18/00153-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2018
• End date: November 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Hélio Zangrossi Júnior
• Grantee: Jhonatan Christian Maraschin
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Panic disorder is characterized by the occurrence of unexpected panic attacks. Studies have shown that activation of the dorsal periaqueductal grey matter (dPAG) evokes behavioural and physiological reactions related to panic. Recently, we showed that administration of bradykinin into the dPAG in rats exposed to the dPAG electrical stimulation test promotes antipanic-like effect. This effect depends on bradykinin B2 receptor (B2R) and µ-opioid receptor (MOR) activation in the dPAG, suggesting the occurrence of heterodimerization or a crosstalk among signalling pathways. In this project we will extend the investigations on the potential of B2R as target for new antipanic drugs development. Our initial aim will be to identify the B2R signalling pathway involved in the antipanic-like effect of bradykinin. For this, we will use biased agonists for G±q, G±i and/or ²-arrestin, that will be administered into the dPAG or intravenously in rats exposed to dPAG electrical stimulation and hypoxia tests. Next, we will perform in vitro assays to characterize the interaction between B2R and MOR. For this, we will use bioluminescence resonance energy transfer (BRET) to observe if these receptors form heterodimers. We will also explore whether there is a crosstalk between signalling pathways recruited by these receptors. Finally, to strengthen the in vitro findings, we will also check, by means of electron microscopy, whether there is a co-localization of B2R and MOR in dPAG neurons.

Scientific publications

(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)

CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, JAN 15 2021. (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)

MARASCHIN, JHONATAN CHRISTIAN; FRIAS, ALANA TERCINO; HERNANDES, PALOMA MOLINA; BATISTELA, MATHEUS FITIPALDI; MARTINEZ, LUCAS MOTTA; LOURENCO JOCA, SAMIA REGIANE; GRAEFF, FREDERICO GUILHERME; AUDI, ELISABETH APARECIDA; CARNEIRO SPERA DE ANDRADE, TELMA GONCALVES; ZANGROSSI JR, HELIO. Antipanic-like effect of esketamine and buprenorphine in rats exposed to acute hypoxia. Behavioural Brain Research, v. 418, FEB 10 2022. (18/00153-5)