RESUMO
It has been shown that AMP-activated protein kinase (AMPK) is involved in the nociceptive processing. This observation has prompted us to investigate the effects of the AMPK activator metformin on the paclitaxel-induced mechanical allodynia, a well-established model of neuropathic pain. Mechanical allodynia was induced by four intraperitoneal (i.p) injections of paclitaxel (2 mg/kg.day) in mice. Metformin was administered per os (p.o.). Naltrexoneandglibenclamide were used to investigate mechanisms mediating metformin activity. Concentrations of cytokines in the dorsal root ganglia (DRG) and thalamus were determined. After a single p.o. administration, the two highest doses of metformin (500 and 1000 mg/kg) attenuated the mechanical allodynia. This response was attenuated by all doses of metformin (250, 500 and 1000 mg/kg) when two administrations, 2 h apart, were carried out. Naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, p.o.), attenuated metformin activity. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and CXCL-1 in the DRG were increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentrations of TNF-α, IL-1ß and CXCL-1 in the DRG. Concentration of IL-6, but not TNF-α, in the thalamus was increased after administration of paclitaxel. Metformin (1000 mg/kg) reduced concentration of IL-6 in the thalamus. In summary, metformin exhibits activity in the model of neuropathic pain induced by paclitaxel. This activity may be mediated by activation of opioidergic pathways and reduced production of TNF-α, IL-1ß and CXCL-1 in the DRG and IL-6 in the thalamus.
Assuntos
Metformina , Neuralgia , Camundongos , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Paclitaxel/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Metformina/farmacologia , Gânglios Espinais/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Interleucina-6/metabolismo , Citocinas/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Tálamo/metabolismoRESUMO
Some B vitamins exhibit activities in models of nociceptive pain, inflammatory pain, and neuropathic pain induced by nerve lesions and also in certain painful conditions in humans. In the present study, we investigated the effects of thiamine, riboflavin, and nicotinamide in a neuropathic pain model induced by the chemotherapeutic paclitaxel in mice. Four intraperitoneal (i.p.) administrations of paclitaxel (2 mg/kg day, cumulative dose 8 mg/kg) induced a long-lasting mechanical allodynia. Per os (p.o.) administration of two doses of thiamine (150, 300 and 600 mg/kg), nicotinamide (250, 500 and 1000 mg/kg) or riboflavin (125, 250 and 500 mg/kg), on the seventh day after the first administration of paclitaxel, the mechanical allodynia was attenuated. The antinociceptive activity of all B vitamins was attenuated by glibenclamide (20 and 10 mg/kg, p.o.). Naltrexone (5 and 10 mg/kg, i.p.) attenuated the antinociceptive activity of thiamine. Thiamine, riboflavin, and nicotinamide also reduced the concentrations of tumor necrosis factor-α (TNF-α) and CXCL-1 in dorsal root ganglia (DRG) and thalamus. In conclusion, thiamine, riboflavin, and nicotinamide exhibit antinociceptive activity in the neuropathic pain model induced by paclitaxel. Inhibition of TNF-α and CXCL-1 production in DRG and thalamus, as well as activation of ATP-sensitive potassium channels, underly their antinociceptive activity.
Assuntos
Quimiocina CXCL1/metabolismo , Gânglios Espinais/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Canais KATP/metabolismo , Tálamo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Complexo Vitamínico B/farmacologia , Animais , Gânglios Espinais/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Niacinamida/farmacologia , Paclitaxel/farmacologia , Riboflavina/farmacologia , Tálamo/metabolismo , Tiamina/farmacologiaRESUMO
BACKGROUND: The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund's adjuvant (CFA) in rats. METHODS: Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500mg/kg) or thiamine (150, 300 or 600mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5mg/kgday, po) was administered every three days. RESULTS: CFA induced long lasting mechanical allodynia and paw edema. Elevation of body temperature was observed for a short period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but partially inhibited mechanical allodynia. Riboflavin (500mg/kg) and thiamine (600mg/kg) exacerbated the anti-inflammatory activity of dexamethasone. Riboflavin, thiamine and dexamethasone reduced TNF-α and IL-6 production. The association of dexamethasone with thiamine induced greater inhibition of IL-6 production when compared with that induced by dexamethasone. CONCLUSIONS: Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.
Assuntos
Citocinas/metabolismo , Dexametasona/uso terapêutico , Adjuvante de Freund/uso terapêutico , Inflamação/tratamento farmacológico , Riboflavina/farmacologia , Tiamina/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Doença Crônica , Citocinas/genética , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Riboflavina/administração & dosagem , Tiamina/administração & dosagemRESUMO
Azadirachta indica (Meliaceae) extracts have been reported to exhibit anti-inflammatory and antinociceptive properties. However, the activities of azadirachtin, a limonoid and the major bioactive compound found in the extracts, have been poorly investigated in animal models. In the present study, we investigated the effects induced by azadirachtin in experimental models of pain and inflammation in mice. Carrageenan-induced paw edema and fibrovascular tissue growth induced by subcutaneous cotton pellet implantation were used to investigate the anti-inflammatory activity of azadirachtin in mice. Zymosan-induced writhing and hot plate tests were employed to evaluate the antinociceptive activity. To explore putative mechanisms of action, the level of tumor necrosis factor-α in inflammatory tissue was measured and the effect induced by opioidergic and serotonergic antagonists was evaluated. Previous per os (p.âo.) administration of azadirachtin (120 mg/kg) significantly reduced the acute paw edema induced by carrageenan. However, the concomitant increase of the paw concentration of tumor necrosis factor-α induced by this inflammatory stimulus was not reduced by azadirachtin. In addition to inhibiting the acute paw edema induced by carrageenan, azadirachtin (6, 60, and 120 mg/kg) inhibited the proliferative phase of the inflammatory response, as demonstrated by the reduced formation of fibrovascular tissue growth. Azadirachtin (120 mg/kg) also inhibited the nociceptive response in models of nociceptive (hot plate) and inflammatory (writhing induced by zymosan) pain. The activity of azadirachtin (120 mg/kg) in the model of nociceptive pain was attenuated by a nonselective opioid antagonist, naltrexone (10 mg/kg, i.âp.), but not by a nonselective serotonergic antagonist, cyproheptadine. In conclusion, this study demonstrates the activity of azadirachtin in experimental models of nociceptive and inflammatory pain, and also in models of acute and chronic inflammation. Finally, multiple mechanisms, including the inhibition of the production of inflammatory mediators and activation of endogenous opioid pathways, may mediate azadirachtin activities in experimental models of inflammation and pain.