ABSTRACT
This study evaluates the pharmacological potential of cis-jasmone (CJ) in adult zebrafish (Danio rerio; aZF). Initially, aZF (n = 6/group) were pretreated (20 µL; p.âo.) with CJ (0.1 or 0.3 or 1.0 mg/mL) or vehicle (0.5% Tween 80). The animals were submitted to acute toxicity and locomotion tests, pentylenetetrazole-induced seizure, carrageenan-induced abdominal edema, and cinnamaldehyde-, capsaicin-, menthol-, glutamate-, and acid saline-induced orofacial nociception. The possible mechanisms of anticonvulsant, anxiolytic, and antinociceptive action were evaluated. The involvement of central afferent fibers sensitive to cinnamaldehyde and capsaicin and the effect of CJ on the relative gene expression of TRPA1 and TRPV1 in the brain of aZF were also analyzed, in addition to the study of molecular docking between CJ and TRPA1, TRPV1 channels, and GABAA receptors. CJ did not alter the locomotor behavior and showed pharmacological potential in all tested models with no toxicity. The anticonvulsant effect of CJ was prevented by flumazenil (GABAergic antagonist). The anxiolytic-like effect of CJ was prevented by flumazenil and serotonergic antagonists. The antinociceptive effect was prevented by TRPA1 and TRPV1 antagonists. Chemical ablation with capsaicin and cinnamaldehyde prevented the orofacial antinociceptive effect of CJ. Molecular docking studies indicate that CJ interacted with TRPA1, TRPV1, and GABAA receptors. CJ inhibited the relative gene expression of TRPA1 and TRPV1. CJ has pharmacological potential for the treatment of seizures, anxiety, inflammation, and acute orofacial nociception. These effects are obtained by modulating the GABAergic and serotonergic systems, as well as the TRPs and ASIC channels.
Subject(s)
Analgesics , Anti-Anxiety Agents , Animals , Analgesics/pharmacology , Analgesics/therapeutic use , Zebrafish/metabolism , Capsaicin/pharmacology , Molecular Docking Simulation , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Flumazenil , gamma-Aminobutyric Acid , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolismABSTRACT
ABSTRACT BACKGROUND AND OBJECTIVES: Adult zebrafish (Danio rerio) has been proposed as a low-cost and simple alternative to the use of rodents in laboratory research on novel compounds with antinociceptive potential. This study aimed to assess whether there is an influence of animal sex and the test environment on the orofacial nociceptive behavior of the adult zebrafish. METHODS: First, cinnamaldehyde, menthol, capsaicin, acidic saline, or glutamate was applied into the lips of the adult male or female zebrafish. Naive groups were included as control. The orofacial nociception was quantified in terms of locomotor activity. In other series of experiments, it was evaluated whether the apparatus, acclimatization, period of test, temperature of the water and color of the open field would alter the nociceptive response to cinnamaldehyde. RESULTS: The nociceptive behavior did not depend on the sex of the animal, apparatus, time the test was performed or the color of the open field. However, acclimatization promoted nociceptive behavior in naive animals and did not alter the nociceptive response to cinnamaldehyde (p<0.01 vs acclimatized naive). The nociception behavior was presented only when the test was performed at a temperature of 26ºC (p<0.01 vs naive). CONCLUSION: The results suggest the need to control the environment and water temperature as an environmental source of variation during the nociceptive behavior test of the adult zebrafish.
RESUMO JUSTIFICATIVA E OBJETIVOS: O peixe-zebra adulto (Danio rerio) tem sido proposto como uma alternativa simples e de baixo custo ao uso de roedores em pesquisas laboratoriais de novos compostos com potencial antinociceptivo. Este estudo teve como objetivo avaliar se há influência do sexo do animal e do ambiente de teste no comportamento nociceptivo orofacial do peixe-zebra adulto. MÉTODOS: Inicialmente, cinamaldeído, mentol, capsaicina, solução salina ácida ou glutamato foi aplicada nos lábios do peixe-zebra adulto masculino ou feminino. Grupos naive foram incluídos como controle. A nocicepção orofacial foi quantificada em termos de atividade locomotora. Em outra série de experimentos, foi avaliado se o aparato, aclimatação, período de teste, temperatura da água e cor do campo aberto alterariam a resposta nociceptiva ao cinamaldeído. RESULTADOS: O comportamento nociceptivo não dependeu do sexo do animal, do equipamento de teste, do horário em que o teste foi realizado ou da cor do campo aberto. No entanto, a aclimatação promoveu comportamento nociceptivo em animais naive e não alterou promoveu comportamento nociceptivo em animais naive e não alterou a resposta nociceptiva ao cinamaldeído (p<0,01 vs naive aclimatado). O comportamento nociceptivo foi verificado apenas quando o teste foi executado a uma temperatura de 26ºC (p<0,01 vs naive). CONCLUSÃO: Os resultados sugerem a necessidade de controlar o ambiente e a temperatura da água como fonte de variação ambiental durante o teste de comportamento nociceptivo do peixe-zebra adulto.
