RESUMO
Drugs used to treat pain are associated with adverse effects, increasing the search for new drugs as an alternative treatment for pain. Therefore, we evaluated the antinociceptive behavior and possible neuromodulation mechanisms of triterpene 3ß, 6ß, 16ß-trihydroxylup-20(29)-ene (CLF-1) isolated from Combretum leprosum leaves in zebrafish. Zebrafish (n = 6/group) were pretreated with CLF-1 (0.1 or 0.3 or 1.0 mg/mL; i.p.) and underwent nociception behavior tests. The antinociceptive effect of CFL-1 was tested for modulation by opioid (naloxone), nitrergic (L-NAME), nitric oxide and guanylate cyclase synthesis inhibitor (methylene blue), NMDA (Ketamine), TRPV1 (ruthenium red), TRPA1 (camphor), or ASIC (amiloride) antagonists. The corneal antinociceptive effect of CFL-1 was tested for modulation by TRPV1 (capsazepine). The effect of CFL-1 on zebrafish locomotor behavior was evaluated with the open field test. The acute toxicity study was conducted. CLF-1 reduced nociceptive behavior and corneal in zebrafish without mortalities and without altering the animals' locomotion. Thus, CFL-1 presenting pharmacological potential for the treatment of acute pain and corneal pain, and this effect is modulated by the opioids, nitrergic system, NMDA receptors and TRP and ASIC channels.
Assuntos
Analgésicos/farmacologia , Combretum/química , Locomoção/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Dor/prevenção & controle , Triterpenos/farmacologia , Canais Iônicos Sensíveis a Ácido/metabolismo , Amilorida/farmacologia , Analgésicos/isolamento & purificação , Animais , Cânfora/farmacologia , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Ketamina/farmacologia , Locomoção/fisiologia , Masculino , Azul de Metileno/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Nociceptividade/fisiologia , Dor/metabolismo , Dor/fisiopatologia , Medição da Dor , Extratos Vegetais/química , Folhas de Planta/química , Receptores de N-Metil-D-Aspartato/metabolismo , Rutênio Vermelho/farmacologia , Canais de Cátion TRPV/metabolismo , Triterpenos/isolamento & purificação , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Thalidomide is a sedative/hypnotic agent that is currently used to treat patients suffering from multiple myeloma, myelodysplastic syndromes and erythema nodosum leprosum. Although previous studies have demonstrated that thalidomide possesses anti-depressant-like properties, the exact mechanism that thalidomide exerts this effect is not understood. In this study, we used two mouse models of depression and investigated the possible role of nitric oxide (NO), NO synthase (NOS) and inducible NOS (iNOS) in the ant-depressant-like effects of thalidomide. METHODS: Male mice were injected with different doses of thalidomide intraperitoneally. In order to assess the anti-depressant-like properties of thalidomide, the immobility time of mice was assessed in the forced swimming test (FST) and tail suspension test (TST). Locomotor activity was assessed using the open-field test. To assess the role of nitric oxide, N(G)-nitro-L-arginine methyl ester (L-NAME, non-specific NOS inhibitor), aminoguanidine (selective iNOS inhibitor) or L-arginine (NO precursor) were administered intraperitoneally along with specific doses of thalidomide. RESULTS: Thalidomide (10â¯mg/kg) significantly reduced immobility time in FST and TST. Aminoguanidine (50â¯mg/kg) and L-NAME (10â¯mg/kg) significantly augmented the anti-immobility effects of thalidomide (5â¯mg/kg). L-arginine (750â¯mg/kg) significantly inhibited the anti-immobility effects of thalidomide (10â¯mg/kg). None of the treatment groups demonstrated alteration of locomotor activity. CONCLUSION: Thalidomide exerts its anti-depressant-like effects through a mechanism dependent upon NO inhibition.