Associação entre buprenorfina e fluoxetina na manifestação de comportamentos defensivos relacionados com a ansiedade generalizada e com o pânico, no labirinto em t elevado
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Data
2018-06-04
Autores
Tiemann-Araújo, Josimarí Cristiane
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Universidade Estadual Paulista (Unesp)
Resumo
Fármacos antidepressivos como os inibidores seletivos de recaptação de serotonina são utilizados no tratamento da ansiedade, pânico e outros transtornos mentais. Os efeitos desejados ocorrem somente após administração crônica, em torno de 3 a 4 semanas após o início do tratamento, com aumento dos sintomas de ansiedade no início da terapia farmacológica, ocasionando a descontinuidade do uso desses fármacos. Além disso, há relatos de resistência a esse tipo de tratamento. Visando encontrar soluções para tais problemas, fundamentados em estudos que mostraram que mecanismos opioides favorecem a atividade inibitória da serotonina em neurônios da Substância Cinzenta Periaquedutal Dorsal que modulam a fuga/pânico, o presente estudo teve por objetivo investigar o efeito da Buprenorfina, um agonista parcial de receptores μ-opioide e antagonista de receptores κ-opioide, como agente ansiolítico e anti-pânico, como também avaliar se o efeito ansiolítico e antipânico da Fluoxetina seriam antecipados pela associação com a Buprenorfina. Foram realizados 3 experimentos utilizando ratos machos Wistar com peso médio de 200g no início das sessões experimentais: 1. Tratamento agudo com Buprenorfina IP nas doses (0,015mg/Kg, 0,03mg/Kg e 0,3mg/Kg), tendo como controle positivo o Alprazolam IP (4mg/Kg); 2. Tratamento subcrônico 3 dias com Buprenorfina IP (0,3mg/Kg); 3. Tratamento agudo com Buprenorfina (0,3mg/Kg) - associado ao tratamento subcrônico com Fluoxetina 3 dias IP (10mg/Kg). Após os tratamentos, os animais foram submetidos à avaliação comportamental no Labirinto em T Elevado (LTE) e, subsequentemente, ao Campo Aberto e ao Teste de Transição Claro-Escuro. No experimento 1 o teste comportamental foi repetido 24 horas após a primeira avaliação comportamental. Os resultados mostraram que a Buprenorfina nas doses maiores diminuiu a latência das esquivas, sem alteração das fugas no LTE, diferentemente do que se constatou no tratamento agudo com o Alprazolam, o qual diminuiu também as esquivas, mas aumentou a latência nas fugas, efeitos esses interpretados respectivamente como, ansiolítico e panicolítico. Vinte e quatro horas depois não se constatou mais efeito do Alprazolam, e o efeito da Buprenorfina sobre as esquivas só foi identificado na maior dose e apenas na LB. Em nenhuma das duas situações houve aumento de atividade motora. No teste de Transição Claro-Escuro não se constatou efeito expressivo nas condições estudadas, apenas possibilitou a escolha da maior dose para a continuidade do estudo, já que a intermediária aumentou a atividade motora nesse teste 24h após a injeção. A Buprenorfina administrada subcronicamente também diminuiu as esquivas, sem afetar a latência das fugas e o comportamento motor no campo aberto. Também não se identificou alterações no Teste de Transição Claro-escuro. A Buprenorfina antecipou o efeito ansiolítico da Fluoxetina, sem afetar as respostas relacionadas com a manifestação do pânico. Entretanto não houve confirmação dos achados no outro teste de ansiedade. Conclui-se que a Buprenorfina, administrada de forma aguda e subcrônica, diminuiu os comportamentos defensivos relacionados com a ansiedade generalizada, e antecipou o efeito ansiolítico da Fluoxetina, podendo se constituir em uma opção relevante no tratamento dos transtornos de ansiedade na clínica, devido à sua baixa capacidade de causar efeitos adversos e também diante da possibilidade de antecipar os efeitos benéficos da fluoxetina, apenas com uma injeção.
Antidepressant drugs such as selective serotonin reuptake inhibitors are used in the treatment of anxiety, panic and other mental disorders. The desired effects occur only after chronic administration, around 3 to 4 weeks after starting treatment, with increased anxiety symptoms at the beginning of pharmacological therapy, causing the discontinuation of the use of these drugs. In addition, there are reports of resistance to this type of treatment. Aiming to find solutions for such problems, based on studies that showed that opioid mechanisms favor the serotonin inhibitory activity in SCPD neurons that modulate scape/panic, the present study aimed to investigate the effect of Buprenorphine, a partial agonist of μ receptors-opioid and antagonist κ receptor-opioid as anxiolytic and anti-panic agents as well as assessing whether the anxiolytic and antipanic effect of Fluoxetine would be antecipated by association with Buprenorphine.Three experiments were performed using male Wistar rats weighing 200g at the beginning of the experimental sessions: 1. Acute treatment with Buprenorphine IP at doses (0,015mg/kg, 0,03mg /kg and 0,3mg/kg) or Alprazolan IP (4mg/kg); 2. Subchronic treatment 3 days with Buprenorphine IP (0,3mg/kg); 3. Acute treatment with Buprenorphine (0,3mg/kg) - associated to the subchronic treatment with Fluoxetine 3 days IP (10mg/kg). After the treatments, the animals were submitted to behavioral evaluation in the Elevated T Maze (ETM) and subsequently to the Open Field and the Light-Dark Transition Test. In experiment 1 the behavioral test was repeated 24 hours after the first behavioral evaluation. The results showed that Buprenorphine in the larger doses decreased the manifestation of the avoidances, without alterations of the scapes in the ETM, differently from what was observed in the acute treatment with Alprazolan, which also reduced the avoidances, but increased the latency in the scapes, results interpreted respectively as anxiolytic and panicolitic. Twenty-four hours later no effect of Alprazolan was found, and the effect of Buprenorphine on the avoidance was only identified at the highest dose and only at LB.There was no increase in motor activity in either of the two situations. In the Light-Dark Transition Test, no significant effect was observed in the conditions studied, it only allowed the choice of the highest dose for the continuity of the study, since the intermediary increased the motor activity in this test 24 hours after the injection.Subchronic administration of Buprenorphine also decreased the avoidances without affecting the scapes and motor behavior in the open field. Also, no changes were identified in the Light-Dark Transition Test. Buprenorphine antecipated the anxiolytic effect of Fluoxetine, without affecting the responses related to the manifestation of panic. However, there was no confirmation of the findings in the other anxiety test. It was concluded that acute and subchronic administration of the Buprenorphine decreased the defensive behaviors related to generalized anxiety, and antecipated the anxiolytic effect of Fluoxetine, which may constitute a relevant option in the treatment of anxiety disorders in the clinic due to the its low ability to cause adverse effects and also the possibility of anticipating the beneficial effects of Fluoxetine with an injection alone.
Antidepressant drugs such as selective serotonin reuptake inhibitors are used in the treatment of anxiety, panic and other mental disorders. The desired effects occur only after chronic administration, around 3 to 4 weeks after starting treatment, with increased anxiety symptoms at the beginning of pharmacological therapy, causing the discontinuation of the use of these drugs. In addition, there are reports of resistance to this type of treatment. Aiming to find solutions for such problems, based on studies that showed that opioid mechanisms favor the serotonin inhibitory activity in SCPD neurons that modulate scape/panic, the present study aimed to investigate the effect of Buprenorphine, a partial agonist of μ receptors-opioid and antagonist κ receptor-opioid as anxiolytic and anti-panic agents as well as assessing whether the anxiolytic and antipanic effect of Fluoxetine would be antecipated by association with Buprenorphine.Three experiments were performed using male Wistar rats weighing 200g at the beginning of the experimental sessions: 1. Acute treatment with Buprenorphine IP at doses (0,015mg/kg, 0,03mg /kg and 0,3mg/kg) or Alprazolan IP (4mg/kg); 2. Subchronic treatment 3 days with Buprenorphine IP (0,3mg/kg); 3. Acute treatment with Buprenorphine (0,3mg/kg) - associated to the subchronic treatment with Fluoxetine 3 days IP (10mg/kg). After the treatments, the animals were submitted to behavioral evaluation in the Elevated T Maze (ETM) and subsequently to the Open Field and the Light-Dark Transition Test. In experiment 1 the behavioral test was repeated 24 hours after the first behavioral evaluation. The results showed that Buprenorphine in the larger doses decreased the manifestation of the avoidances, without alterations of the scapes in the ETM, differently from what was observed in the acute treatment with Alprazolan, which also reduced the avoidances, but increased the latency in the scapes, results interpreted respectively as anxiolytic and panicolitic. Twenty-four hours later no effect of Alprazolan was found, and the effect of Buprenorphine on the avoidance was only identified at the highest dose and only at LB.There was no increase in motor activity in either of the two situations. In the Light-Dark Transition Test, no significant effect was observed in the conditions studied, it only allowed the choice of the highest dose for the continuity of the study, since the intermediary increased the motor activity in this test 24 hours after the injection.Subchronic administration of Buprenorphine also decreased the avoidances without affecting the scapes and motor behavior in the open field. Also, no changes were identified in the Light-Dark Transition Test. Buprenorphine antecipated the anxiolytic effect of Fluoxetine, without affecting the responses related to the manifestation of panic. However, there was no confirmation of the findings in the other anxiety test. It was concluded that acute and subchronic administration of the Buprenorphine decreased the defensive behaviors related to generalized anxiety, and antecipated the anxiolytic effect of Fluoxetine, which may constitute a relevant option in the treatment of anxiety disorders in the clinic due to the its low ability to cause adverse effects and also the possibility of anticipating the beneficial effects of Fluoxetine with an injection alone.
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Palavras-chave
Buprenorfina., Fluoxetina., Labirinto em T Elevado., Receptores opioides., Transtorno de Ansiedade Generalizada., Transtorno do Pânico.