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Involvement of locus coeruleus neural pathways and noradrenergic neurotransmission in the dorsal raphe nucleus in antinociceptive processes induced by oriented escape reactions evoked by chemical stimulation of the medial hypothalamus

Grant number: 09/01153-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): September 01, 2009
Effective date (End): October 31, 2010
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Norberto Cysne Coimbra
Grantee:Andres Uribe Marino
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The encephalic aversion system is composed of different mesencephalic and prosencephalic structures such as the periaqueductal gray matter, deep layers of the superior colliculus, central nucleus of the inferior colliculus, amygdala and medial hypothalamus. These areas constitute the main neural substrate for the integration of aversive states in the central nervous system. Thus, chemical and electrical stimulation procedures of brainstem regions elicit explosive defensive responses related to fear and similar to those exhibited by patients with panic disorder. However, analogous techniques applied in different medial hypothalamic nuclei produce less intense and more organized escape behaviors. Generally, after stimulation of these structures, antinociceptive processes are observed which are modulated by several chemical substances of opioid and non-opioid nature in midbrain and some nuclei of the pain inhibitory endogenous system and hypothalamic complex regulated by inhibitory GABAergic projections.The objective of the present research project consists in the establishment of connections between ventro-medial hypothalamus (VMH) and dorso-medial hypothalamus (DMH) with monoaminergic nuclei of the pain inhibitory endogenous system , such as the dorsal raphe nucleus (DRN) and Locus coeruleus (LC), through a neuroanatomical study with iontophoretic microinjections of an anterograde and retrograde neurotracer, Biodextran combined with Texas Red or fluorescein in each hypothalamic nuclei studied, followed by inmunohistochemical reactions for the identification of positive neurons for Tyrosine Hydroxylase. Another study will be made on the effects of the neurotoxic lesion with specific neurotoxins for noradrenergic neurons in the LC, that possibly have direct or indirect connections with VMH and DMH and have some role in the analgesia induced by evoked fear after the chemical stimulation of the VMH and DMH. In independent groups of animals, the effects of pre-treatment with microinjections of noradrenergic antagonists in the DRN will be determined, a structure that posses reciprocal connections with the LC, to evaluate the involvement of the coeruleus-dorsal raphe pathway on pain control during the organization of antinociception induced by oriented escape behaviors.

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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)
URIBE-MARINO, ANDRES; FRANCISCO, AUDREY; CASTIBLANCO-URBINA, MARIA ANGELICA; TWARDOWSCHY, ANDRE; SALGADO-ROHNER, CARLOS JOSE; CRIPPA, JOSE ALEXANDRE S.; CECILIO HALLAK, JAIME EDUARDO; ZUARDI, ANTONIO WALDO; COIMBRA, NORBERTO CYSNE. Anti-Aversive Effects of Cannabidiol on Innate Fear-Induced Behaviors Evoked by an Ethological Model of Panic Attacks Based on a Prey vs the Wild Snake Epicrates cenchria crassus Confrontation Paradigm. NEUROPSYCHOPHARMACOLOGY, v. 37, n. 2, p. 412-421, . (09/01153-0, 08/08955-1, 08/00531-8, 09/01157-5)
TWARDOWSCHY, ANDRE; CASTIBLANCO-URBINA, MARIA ANGELICA; URIBE-MARINO, ANDRES; BIAGIONI, AUDREY FRANCISCO; SALGADO-ROHNER, CARLOS JOSE; DE SOUZA CRIPPA, JOSE ALEXANDRE; COIMBRA, NORBERTO CYSNE. The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae). JOURNAL OF PSYCHOPHARMACOLOGY, v. 27, n. 12, p. 11-pg., . (09/01157-5, 09/01153-0, 08/00531-8, 08/08955-1, 10/15140-4)
FREITAS, RENATO LEONARDO; URIBE-MARINO, ANDRES; CASTIBLANCO-URBINA, MARIA ANGELICA; ELIAS-FILHO, DAOUD HIBRAIM; COIMBRA, NORBERTO CYSNE. GABA(A) receptor blockade in dorsomedial and ventromedial nuclei of the hypothalamus evokes panic-like elaborated defensive behaviour followed by innate fear-induced antinociception. Brain Research, v. 1305, p. 118-131, . (09/01153-0)

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