Avaliação dos substratos neurais do efeito ansiogênico da substância P

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Curso de Pós-Graduação em FarmacologiaO presente trabalho investigou o substrato neuroanatômico e o envolvimento dos receptores taquicinérgicos NK1 e NK2 na área de maior relevância para o efeito ansiogênico induzido pela SP em ratos avaliados no teste do labirinto em cruz elevado (LCE). Nossos dados mostram que os ratos tratados com SP 10 pmol no septo lateral (SL) expressaram reações de defesa extremas no teste do LCE e na arena, denominadas como respostas de "freezing" e "darting", respectivamente, sendo essa ação muito mais evidente nessa área do que quando a SP foi injetada na região amigdalar ou no ventrículo lateral. Por outro lado, a injeção intra-septal de FK 888 (100 pmol), antagonista NK1, ou de SR 48968 (100 pmol), antagonista NK2, no SL, seguido da injeção de SP (10 pmol) no ventrículo lateral foi capaz de inibir as respostas aversivas induzidas pela injeção intracerebroventricular de SP. Estes resultados sugerem que o septo lateral parece ser um substrato neuroanatômico muito importante na mediação dos efeitos do tipo ansiogênico da SP e que os receptores NK1 e NK2 possuem um papel importante na mediação deste efeito

Participação do sistema nociceptina/orfanina fq-receptor nop na modulação da ansiedade e da depressão experimental

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em FarmacologiaO presente trabalho estudou o papel da nociceptina (N/OFQ) e da nocistatina (NST) na modulação da ansiedade e da depressão experimental. Nossos dados mostraram que camundongos tratados com N/OFQ apresentaram um perfil do tipo ansiolítico no teste do labirinto em cruz elevado (LCE), enquanto que a NST induziu um efeito do tipo ansiogênico. Além disso, dados mostrados neste trabalho sugerem haver uma interação entre o sistema GABAérgico e a N/OFQ, mas não entre a NST, na modulação da ansiedade experimental. Em relação à depressão experimental, observamos que a N/OFQ e a NST não alteraram o comportamento dos camundongos submetidos ao teste da natação forçada (TNF), porém o UFP-101, um antagonista NOP, induziu um perfil do tipo antidepressivo no TNF em camundongos e ratos e no teste da suspensão pela cauda (TSC) em camundongos e, em linha com estes dados, camundongos knockout para o receptor NOP apresentaram um perfil do tipo antidepressivo no TNF e no TSC. No presente trabalho mostrou-se também que o efeito do tipo antidepressivo induzido pelo bloqueio do receptor NOP parece ser mediado pelo sistema monaminérgico e, em especial, pelo serotonérgico. Assim, os resultados apresentados nesta tese candidatam o sistema N/OFQ - receptor NOP como um alvo terapêutico promissor para o tratamento da ansiedade e da depressão

Antidepressant- and anxiolytic-like effects of nociceptin/orphanin FQ receptor ligands

Many studies point toward the nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP) as targets for the development of innovative drugs for treating affective disorders. It has been reported that the activation of NOP receptors produces anxiolytic-like effects in rodents in a large series of behavioral assays, i.e., elevated plus maze, light-dark aversion, operant conflict, fear-potentiated startle, pup ultrasonic vocalizations, and hole board tests. In contrast, the blockade of N/OFQ signaling obtained with NOP-selective antagonists promotes antidepressant-like effects in the forced swimming and tail suspension tests. In these assays, N/OFQ is inactive per se, but reverses the antidepressant-like effects of NOP antagonists. NOP receptor knockout mice show an antidepressant-like phenotype, and NOP antagonists are inactive in these animals. Thus, the activation of the NOP receptor seems to evoke anxiolytic-like effects while its blockade antidepressant-like effects. This appears to be a rather unique behavioral profile since the activation or the blockade of a given neuropeptide receptor produces, in most of the cases, both antidepressant- and anxiolytic-like effects. This particular behavioral profile, the possible mechanisms of action, and the therapeutic potential of NOP receptor ligands for the treatment of depression and anxiety disorders are discussed in this review article

ANTAGONISTI DEL RECETTORE UT E LORO USI TERAPEUTICI

La presente invenzione riguarda l\u2019uso di composti in grado di bloccare o inibire i recettori UT per la preparazione di composizioni farmaceutiche utili per il trattamento dell\u2019ansia e della depressione o dei disturbi clinicamente correlati. I composti utilizzabili secondo l\u2019invenzione possono essere peptidi, derivati peptidici o molecole non-peptidiche, con propriet\ue0 di antagonisti o agonisti parziali dei recettori UT. Tali composti possono essere utilizzati in combinazione con altre sostanze attive usate nella terapia della depressione e dell\u2019ansia o dei disturbi ad essi correlati

ANTAGONISTI DEL RECETTORE UT E LORO USI TERAPEUTICI

La presente invenzione riguarda l’uso di composti in grado di bloccare o inibire i recettori UT per la preparazione di composizioni farmaceutiche utili per il trattamento dell’ansia e della depressione o dei disturbi clinicamente correlati. I composti utilizzabili secondo l’invenzione possono essere peptidi, derivati peptidici o molecole non-peptidiche, con proprietà di antagonisti o agonisti parziali dei recettori UT. Tali composti possono essere utilizzati in combinazione con altre sostanze attive usate nella terapia della depressione e dell’ansia o dei disturbi ad essi correlati

Altered anxiety-related behavior in nociceptin/orphanin FQ receptor gene knockout mice

Studies showed that nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) agonists produce anxiolytic-like actions, while little is known about the effects of blockade of NOP receptor signaling in anxiety. To this aim, we investigated the behavioral phenotype of NOP receptor gene knockout mice (NOP(-/-)) in different assays. In the elevated plus-maze and light-dark box, NOP(-/-) mice displayed increased anxiety-related behavior. In the novelty-suppressed feeding behavior and elevated T-maze, NOP(-/-) mice showed anxiolytic-like phenotype, while no differences were found in the open-field, hole-board, marble-burying, and stress-induced hyperthermia. Altogether, these findings suggest that the N/OFQ-NOP receptor system modulates anxiety-related behavior in a complex manner

Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8 ,9-tetrahydro-5H-benzocyclohepten-5-ol]: In vivo studies

The excellent pharmacological profile displayed by the selective nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] in vitro prompted us to investigate the actions of this compound in vivo. In the mouse tail withdrawal assay, SB-612111 given i.p. up to 3 mg/kg did not modify per se tail withdrawal latencies but was able to prevent the pronociceptive and the antinociceptive action of 1 nmol of N/OFQ given i.c.v. and i.t., respectively. In food intake studies performed in sated mice, SB-612111 (1 mg/kg i.p.) had no effect on food consumption but fully prevented the orexigenic effect of 1 nmol of N/OFQ i.c.v. In 17-h food-deprived mice, the opioid receptor antagonist naltrexone (1 mg/kg s.c.), but not SB-612111 (1 and 10 mg/kg i.p.), produced a statistically significant reduction of food intake. In the mouse forced swimming and tail suspension tests, SB-612111 (1-10 mg/kg) reduced immobility time. The antidepressant-like effect elicited by SB-612111 in the forced swimming test was reversed by the i.c.v. injection of 1 nmol of N/OFQ and no longer evident in mice knockout for the NOP receptor gene. In conclusion, the present findings demonstrate that SB-612111 behaves in vivo as a potent and selective NOP antagonist and suggest that the N/OFQ-NOP receptor endogenous system plays an important role in regulating mood-related behaviors. The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas

Short- and long-term anxiogenic effects induced by a single injection of subconvulsant doses of pilocarpine in rats: investigation of the putative role of hippocampal pathways

Behavioral consequences of convulsive episodes are well documented, but less attention was paid to changes that occur in response to subconvulsant doses of drugs. We investigated short- and long-term effects of a single systemic injection of a subconvulsant dose of pilocarpine on the behavior of rats as evaluated in the elevated plus maze. Pilocarpine induced an anxiogenic-like profile 24 h later, and this effect persisted for up to 3 months (% of time spent on open arms at 24 h, control = 35.47 +/- 3.23; pilocarpine 150 = 8.2 +/- 2.6; 3 months, control = 31.9 +/- 5.5; pilocarpine 150 = 9.3 +/- 4.9). Temporary inactivation of fimbria-fornix with lidocaine 4% promoted an anxiolytic-like effect per se, suggesting a tonic control of this pathway on the modulation of anxiety-related behaviors. Lidocaine also reduced the anxiogenic-like profile of animals tested 1 month after pilocarpine treatment (% of time spent on open arms, saline + phosphate-buffered saline (PBS) = 31.7 + 3.7; saline + lidocaine = 54.4 + 4.7; pilocarpine + PBS = 10.3 + 4.1; pilocarpine + lidocaine = 40.1 + 9.1). To determine whether the anxiogenic-like effect was mediated by septal region or by direct hippocampal projections to the diencephalon, the neural transmission of post-commissural fornix was blocked, and a similar reduction in the anxiogenic-like effect of pilocarpine was observed. Our findings suggest that a single systemic injection of pilocarpine may induce long-lasting anxiogenic-like behavior in rats, an effect that appears to be mediated, in part, through a direct path from hippocampus to medial hypothalamic sites involved in fear responses.Brazilian National Research Council (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CAPESCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNP

Anxiolytic and antidepressant-like activities of UFP-512, a novel selective delta opiold receptor agonist

A large body of evidence emerging from pharmacological and knockout studies suggests the involvement of the delta opioid peptide (DOP) receptor in the control of anxiety and depression