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Social defeat-induced antinociception: implication of spinal and supraspinal vanilloid neurotransmission in mice.

Grant number: 13/06764-2
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2013
Effective date (End): July 31, 2017
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Ricardo Luiz Nunes de Souza
Grantee:Diego Cardozo Mascarenhas
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Acute stress suppresses pain by activating brain pathways that engage opioid and non-opioid mechanisms. Stress-induced analgesia (SIA) can be induced by various stressors, e.g. the social defeat. Nociceptive tests are often used to assess this antinociception, among them stands out the tail-flick test, which consist in a phasic pain test. The SIA is, at least partially, modulated by endovanilloid compounds, which are substances that activate the TRPV1 (Transient Receptor Potential vanilloid type-1; also known as vanilloid receptors). The TRPV1 are excitatory ion channels, permeable to calcium and are present at both spinal (dorsal horn of the spinal cord) and supraspinal [e.g., dorsal Periaqueductal Gray Matter (dPAG)] levels. The endocannabinoids (e.g., anandamide) which activate the cannabinoid type 1 receptor (CB1 - inhibitory metabotropic receptor), are also involved with the vanilloids in this modulation, since these compounds activate both systems. In this context, this proposal aims to elucidate the implications of supraspinal and spinal vanilloid neurotransmission, in the social defeat-induced analgesia in mice subjected to the tail-flick test. Initially it will be performed a dose response curve with AM251 (CB1 antagonist), capsazepine (TRPV1 antagonist), anandamide (endogenous TRPV1 agonist), capsaicin (TRPV1 agonist) and cyclosporin A (phosphatase 2B inhibitor - enzyme responsible for dephosphorylating the TRPV1 channel and render it insensitive to endogenous ligands) in order to elucidate their participation at both spinal and supraspinal (dPAG) levels in the modulation of the nociceptive response assessed in the tail-flick test. Then, in order to evaluate the involvement of vanilloid and cannabinoid receptors in the modulation of the social defeat-induced analgesia, it will be performed the TRPV1 and CB1 receptors blockade through the antagonists capsazepine and AM251, respectively, at a dose devoid of effect on nociception at spinal and supraspinal (dPAG) levels in socially defeated animals. Finally, aiming to evaluate the role of TRPV1 channel on its phosphorylated state (i.e., sensitive to endogenous ligands) in the modulation of the social defeat-induced antinociception, intrathecal and intra-dPAG microinjections of cyclosporin A, a compound that retains the TRPV1 channel on its phosphorylated state, will be injected in mice.

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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)
MASCARENHAS, DIEGO CARDOZO; GOMES, KARINA SANTOS; NUNES-DE-SOUZA, RICARDO LUIZ. Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice. Behavioural Brain Research, v. 292, p. 547-554, . (13/03445-3, 13/01283-6, 13/06764-2)
SORREGOTTI, TATIANI; CIPRIANO, ANA CLAUDIA; CRUZ, FABIO CARDOSO; MASCARENHAS, DIEGO CARDOZO; RODGERS, ROBERT JOHN; NUNES-DE-SOUZA, RICARDO LUIZ. Amygdaloid involvement in the defensive behavior of mice exposed to the open elevated plus-maze. Behavioural Brain Research, v. 338, p. 159-165, . (13/06764-2, 14/02956-7, 11/04561-1, 13/01283-6, 13/24986-2)
MASCARENHAS, DIEGO C.; GOMES, KARINA S.; SORREGOTTI, TATIANI; NUNES-DE-SOUZA, RICARDO L.. Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice. FRONTIERS IN PHARMACOLOGY, v. 8, . (13/01283-6, 13/06764-2, 13/03445-3)

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