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
Cannabidiol (CBD) is a substance that exerts several therapeutic actions, including analgesia. CBD is generally administered orally, but its poor water solubility and metabolism impair its bioavailability. Thus, the development of molecules with better pharmacokinetic profile from cannabidiol becomes an interesting strategy for the design of novel analgesic drugs for the relief of painful conditions that are difficult to manage clinically, such as neuropathic pain. In the present study, an unprecedented analogue of CBD (1) was synthesized and some of its physicochemical properties were evaluated inâ silico as well as its stability in an acid medium. Additionally, its effect was investigated in a model of neuropathic pain induced by the chemotherapy drug paclitaxel in mice, in comparison with cannabidiol itself. Cannabidiol (20â mg/kg), pregabalin (30â mg/kg), or analogue 1 (5, 10, and 20â mg/kg), administered on the 14th day after the first administration of paclitaxel, attenuated the mechanical allodynia of the sensitized animals. The antinociceptive activity of analogue 1 was attenuated by previous administration of a cannabinoid CB1 receptor antagonist, AM 251, which indicates that its mechanism of action is related to the activation of CB1 receptors. In conclusion, the CBD analogue 1 developed in this study shows great potential to be used in the treatment of neuropathic pain.
Assuntos
Canabidiol , Neuralgia , Camundongos , Animais , Canabidiol/efeitos adversos , Modelos Animais de Doenças , Neuralgia/tratamento farmacológico , Neuralgia/induzido quimicamente , Paclitaxel/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêuticoRESUMO
Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1 h) per os (p.o.) administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600 µg) and also the pleurisy induced by this stimulus (200 µg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1 h) the inflammatory stimulus. Metformin (1000 mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10 mg/kg, intraperitoneal) or cyproheptadine (5 or 10 mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40 mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Neuralgia , Trifosfato de Adenosina , Animais , Carragenina , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Neuralgia/tratamento farmacológico , Canais de Potássio , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Curcumin and its analogues exhibited anti-inflammatory activity in different experimental models. Recently, we synthesized (2E,3E)-3-buten-2-one-4-(4-hydroxy-3-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-thiazolyl)hydrazone (RI75), a curcumin analogue with a thiazolyl hydrazone moiety. In the present study, we investigated the effects induced by RI75 in different models of inflammation and pain in mice, as well as some underlying mechanisms. Pre-treatment with RI75 (40 mg/kg, intraperitoneal; i.p.) or curcumin (40 mg/kg, i.p.) reduced the mechanical allodynia and paw edema induced by intraplantar (i.pl) injection of carrageenan. RI75 antiallodynic activity was reduced by pre-treatment with naltrexone (5 and 10 mg/kg, i.p.) and cyproheptadine (10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, i.p.). In a model of neuropathic pain, a single i.p. administration of RI75 (40 mg/kg) or curcumin (40 mg/kg) attenuated the ongoing mechanical allodynia induced by repeated administrations of paclitaxel. Pre-treatment with RI75 (40 mg/kg, i.p.) or curcumin (40 mg/kg, i.p.) also reduced tumor necrosis factor-α and interleukin-6 production and myeloperoxidase activity induced by carrageenan. The results of the present study demonstrate that RI75, a synthetic curcumin analogue, exhibits antiallodynic and antiedematogenic activities. Activation of opioidergic and serotonergic mechanisms and reduced production of inflammatory mediators and neutrophil recruitment may underlie RI75 activities.
Assuntos
Curcumina , Hiperalgesia , Interleucina-6 , Neuralgia , Fator de Necrose Tumoral alfa , Animais , Curcumina/análogos & derivados , Curcumina/farmacologia , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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
Clindamycin, a bacteriostatic semisynthetic lincosamide, is useful in the management of infections caused by aerobic and anaerobic Gram-positive cocci, including bacteremic pneumonia, streptococcal toxic shock syndrome and sepsis. It has been recently demonstrated that clindamycin inhibits in vitro and in vivo inflammatory cytokine production. In the present study, we investigated the effects of clindamycin in acute and chronic models of pain and inflammation in mice and the underlying mechanisms. Intraperitoneal (i.p.) administration of clindamycin (400 mg/kg) increased the animal's latency to exhibit the nociceptive behavior induced by noxious heat (hot plate model). Intrathecal injection of clindamycin (2, 10 and 50 µg) also increased the animals' latency to exhibit the nociceptive behavior. Tactile hypersensitivity and paw edema induced by intraplantar (i.pl.) injection of carrageenan were attenuated by previous administration of clindamycin (200 and 400 mg/kg, i.p.). Clindamycin (100, 200 and 400 mg/kg, i.p.) also attenuated ongoing tactile hypersensitivity and paw edema induced by i.pl. injection of complete Freund's adjuvant (CFA). The antinociceptive activity of clindamycin (400 mg/kg, i.p.) in the hot plate model was attenuated by previous administration of naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide or AM251. CFA-induced production of TNF-α and CXCL-1 was reduced by clindamycin (400 mg/kg, i.p.). Concluding, clindamycin exhibits activities in acute and chronic models of pain and inflammation. These effects are associated with reduced production of TNF-α and CXCL-1 and activation of opioidergic mechanisms. Altogether, these results indicate that the clindamycin's immunomodulatory effects may contribute to a pharmacological potential beyond its antibiotic property.
Assuntos
Clindamicina/farmacologia , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Carragenina , Quimiocina CXCL1/metabolismo , Clindamicina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/patologia , Inflamação/patologia , Masculino , Camundongos , Dor/patologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.
Assuntos
Analgésicos/síntese química , Nicorandil/química , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Meia-Vida , Isomerismo , Camundongos , Nicorandil/farmacocinética , Nicorandil/uso terapêutico , Dor/tratamento farmacológicoRESUMO
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.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Azadirachta/química , Edema/tratamento farmacológico , Limoninas/farmacologia , Extratos Vegetais/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Carragenina/efeitos adversos , Modelos Animais de Doenças , Edema/induzido quimicamente , Feminino , Inflamação/tratamento farmacológico , Limoninas/química , Limoninas/isolamento & purificação , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: When exacerbated, inflammatory processes can culminate in physical and emotional disorders and, if not stopped, can be lethal. The high prevalence of inflammation has become a public health problem, and the need for new drugs to treat this pathology is imminent. The use of medicinal plants has emerged as an alternative, and a survey of data that corroborates its application in inflammatory diseases is the starting point. Furthermore, Brazil harbors a megadiversity, and the traditional use of plants is relevant and needs to be preserved and carefully explored for the discovery of new medicines. AIM OF THE STUDY: This review sought to survey the medicinal plants traditionally used in Brazil for the treatment of inflammatory processes and to perform, in an integrative way, a data survey of these species and analysis of their phytochemical, pharmacological, and molecular approaches. MATERIALS AND METHODS: Brazilian plants that are traditionally used for inflammation (ophthalmia, throat inflammation, orchitis, urinary tract inflammation, ear inflammation, and inflammation in general) are listed in the DATAPLAMT database. This database contains information on approximately 3400 native plants used by Brazilians, which were registered in specific documents produced until 1950. These inflammatory disorders were searched in scientific databases (PubMed/Medline, Scopus, Web of Science, Lilacs, Scielo, Virtual Health Library), with standardization of DECS/MESH descriptors for inflammation in English, Spanish, French, and Portuguese, without chronological limitations. For the inclusion criteria, all articles had to be of the evaluated plant species, without association of synthesized substances, and full articles free available in any of the four languages searched. Duplicated articles and those that were not freely available were excluded. RESULTS: A total of 126 species were identified, culminating in 6181 articles in the search. After evaluation of the inclusion criteria, 172 articles representing 40 different species and 38 families were included in the study. Comparison of reproducibility in intra-species results became difficult because of the large number of extraction solvents tested and the wide diversity of evaluation models used. Although the number of in vitro and in vivo evaluations was high, only one clinical study was found (Abrus precatorius). In the phytochemical analyses, more than 225 compounds, mostly phenolic compounds, were identified. CONCLUSION: This review allowed the grouping of preclinical and clinical studies of several Brazilian species traditionally used for the treatment of many types of inflammation, corroborating new searches for their pharmacological properties as a way to aid public health. Furthermore, the large number of plants that have not yet been studied has encouraged new research to revive traditional knowledge.
Assuntos
Anti-Inflamatórios , Etnofarmacologia , Medicina Tradicional , Fitoterapia , Plantas Medicinais , Brasil , Humanos , Plantas Medicinais/química , Etnofarmacologia/métodos , Medicina Tradicional/métodos , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Animais , Inflamação/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/farmacologia , Preparações de Plantas/uso terapêutico , Preparações de Plantas/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/farmacologiaRESUMO
BACKGROUND: Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. METHODS: CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). RESULTS: Oral administration of two doses of nicorandil (150 mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40 mg/kg) or naltrexone (5 mg/kg or 10 mg/kg). Two doses of nicorandil (150 mg/kg, po) reduced tumor necrosis factor-α, interleukin-1ß and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150 mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150 mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. CONCLUSIONS: Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.
RESUMO
Hydrogen sulfide (H2S) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both H2S donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel H2S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-H2S), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-H2S (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-H2S (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-H2S (25 mg/kg, i.p.) was more sustained than that induced by the H2S donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-H2S antiallodynic activity. In conclusion, we synthesized a novel H2S-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-H2S activity may be due to H2S release and activation of ATP-sensitive potassium channels. The demonstration of PTD-H2S activity in models of pain stimulates further studies aiming to evaluate H2S-releasing phthalimide hybrids as candidates for analgesic drugs.
Assuntos
Sulfeto de Hidrogênio , Hiperalgesia , Camundongos , Animais , Tionas , Isoindóis , Lipopolissacarídeos , Dor/tratamento farmacológico , Ftalimidas/farmacologia , Ftalimidas/uso terapêutico , Ftalimidas/químicaRESUMO
We recently demonstrated that clindamycin exhibits activities in acute and chronic models of pain and inflammation. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced in mice by intraarticular (i.a.) injection of zymosan or lipopolysaccharide (LPS). Clindamycin or CAD were administered via the intraperitoneal route 1 h before zymosan or LPS. Paw withdrawal threshold, joint diameter, histological changes, neutrophil recruitment, tumor necrosis factor-α (TNF-α) production and phosphorylation of the IκBα and NF-κB/p65 were evaluated. In vitro assays were used to measure the antibacterial activity of clindamycin and CAD and also their effects on zymosan-induced TNF-α production by RAW264.7 macrophages. Clindamycin exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains at much lower concentrations than CAD. Intraarticular injection of zymosan or LPS induced articular hyperalgesia, edema and neutrophil infiltration in the joints. Zymosan also induced histological changes, NF-κB activation and TNF-α production. Responses induced by zymosan and LPS were inhibited by clindamycin (200 and 400 mg/kg) or CAD (436 mg/kg). Both clindamycin and CAD inhibited in vitro TNF-α production by macrophages. In summary, we provided additional insights of the clindamycin immunomodulatory effects, whose mechanism was associated with NF-κB inhibition and reduced TNF-α production. Such effects were extended to a clindamycin derivative with reduced antibacterial activity, indicating that clindamycin derivatives should be investigated as candidates to drugs that could be useful in the management of inflammatory and painful conditions.
Assuntos
Artrite , NF-kappa B , Camundongos , Animais , Fator de Necrose Tumoral alfa/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Clindamicina/uso terapêutico , Clindamicina/farmacologia , Infiltração de Neutrófilos , Zimosan , Lipopolissacarídeos/farmacologia , Inflamação/induzido quimicamente , Antibacterianos/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológicoRESUMO
Metformin, an AMP-activated protein kinase (AMPK) activator, is an oral hypoglycemic drug widely used to treat patients with type 2 diabetes. As AMPK plays a role in the nociceptive processing, investigating the effects induced by metformin in experimental models of pain is warranted. In the present study, we further evaluated the effects induced by metformin in models of nociceptive and neuropathic pain and investigated mechanisms that could mediate such effects. Metformin was administered per os (p.o.) in mice. Nociceptive response induced by heat (hot-plate) and mechanical allodynia induced by chronic constriction injury (CCI) were used as pain models. Naltrexone (intraperitoneal) and glibenclamide (p.o.) were used to investigate mechanisms mediating metformin effects. A single administration of metformin (500 or 1000â¯mg/kg) inhibited the nociceptive response in the hot-plate model. Single and repeated administration of metformin (250, 500 or 1000â¯mg/kg) inhibited the mechanical allodynia induced by CCI. Metformin (250, 500 or 1000â¯mg/kg) did not affect the time mice spent in the rota-rod apparatus. The activity of metformin (1000â¯mg/kg) in both pain models was attenuated by naltrexone (10â¯mg/kg), but not by glibenclamide. Concluding, metformin exhibited activity in models of nociceptive and neuropathic pain. In the model of neuropathic pain, preventive and therapeutic effects were observed. Activation of opioidergic pathways partially mediates metformin antinociceptive activity. Altogether, the results indicate that metformin should be further investigated aiming its repositioning in the treatment of patients with different painful conditions.
Assuntos
Analgésicos/farmacologia , Metformina/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Glibureto/farmacologia , Hiperalgesia/tratamento farmacológico , Metformina/uso terapêutico , Camundongos , Naltrexona/farmacologia , Neuralgia/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacosRESUMO
The gasotransmitter hydrogen sulfide (H2S) is known to regulate many pathophysiological processes. Preclinical assays have demonstrated that H2S donors exhibit anti-inflammatory and antinociceptive activities, characterized by reduction of inflammatory mediators production, leukocytes recruitment, edema and mechanical allodynia. In the present study, the effects induced by 4-methylbenzenecarbothioamide (4-MBC) in models of pain and inflammation in mice, the mechanisms mediating such effects and the H2S-releasing property of this compound were evaluated. 4-MBC spontaneously released H2S in vitro in the absence of organic thiols. Intraperitoneal (i.p.) administration of 4-MBC (100 or 150â¯mg/kg) reduced the second phase of the nociceptive response induced by formaldehyde and induced a long lasting inhibitory effect on carrageenan mechanical allodynia. 4-MBC antiallodynic effect was not affected by previous administration of naltrexone or glibenclamide. 4-MBC (50, 100 or 150â¯mg/kg, i.p.) induced a long lasting inhibitory effect on paw edema induced by carrageenan. The highest dose (150â¯mg/kg, i.p.) of 4-MBC inhibited tumor necrosis factor-α and CXCL1 production and myeloperoxidase activity induced by carrageenan. Mechanical allodynia and paw edema induced by carrageenan were not inhibited by the 4-MBC oxo analogue (p-toluamide). In summary, 4-MBC, an H2S releasing thiobenzamide, exhibits antinociceptive and anti-inflammatory activities. These activities may be due to reduced cytokine and chemokine production and neutrophil recruitment. The H2S releasing property is likely essential for 4-MBC activity. Our results indicate that 4-MBC may represent a useful pharmacological tool to investigate the biological roles of H2S.
Assuntos
Amidas/farmacologia , Derivados de Benzeno/farmacologia , Quimiocina CXCL1/biossíntese , Sulfeto de Hidrogênio/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Tioamidas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Amidas/uso terapêutico , Animais , Derivados de Benzeno/química , Derivados de Benzeno/uso terapêutico , Modelos Animais de Doenças , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Tioamidas/química , Tioamidas/uso terapêuticoRESUMO
BACKGROUND: Phthalimide analogues devoid of the glutarimide moiety exhibit multiple biological activities, thus making them candidates for the treatment of patients with different diseases, including those with inflammatory and painful disorders. In the present study, the activities of five phthalimide analogues devoid of the glutarimide moiety (N-hydroxyphthalimide, N-hydroxymethylphthalimide, N-3-hydroxypropylphthalimide, N-carboxy-3-methylphthalimide, N-carboxymethyl-3-nitrophthalimide) were evaluated in experimental models of acute and chronic inflammatory and neuropathic pain. METHODS: The phthalimide analogues were administered per os (po) in Swiss mice or Wistar rats. Nociceptive response induced by formaldehyde and mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve or intraplantar (ipl) injection of complete Freund's adjuvant (CFA) were used as experimental models of pain. RESULTS: N-carboxymethyl-3-nitrophthalimide (700â¯mg/kg, -1â¯h) inhibited the second phase of the nociceptive response induced by the intraplantar injection of formaldehyde in mice. N-3-hidroxypropylphthalimide (546â¯mg/kg, -1â¯h) inhibited both phases of the nociceptive response induced by formaldehyde. Treatment of rats with N-carboxymethyl-3-nitrophthalimide (700â¯mg/kg) or N-3-hydroxypropylphthalimide (546â¯mg/kg) inhibited the mechanical allodynia induced by CCI of the sciatic nerve or ipl injection of CFA in rats. Intraperitoneal administration of the opioid antagonist naltrexone (10â¯mg/kg, -1.5â¯h) attenuated the antinociceptive activity of N-carboxymethyl-3-nitrophthalimide (700â¯mg/kg) in the model of nociceptive response induced by formaldehyde. CONCLUSIONS: N-3-hydroxypropylphthalimide and N-carboxymethyl-3-nitrophthalimide, two phthalimide analogues devoid of the glutarimide moiety, exhibited activities in different experimental models of pain, including models of chronic inflammatory and neuropathic pain.
Assuntos
Inflamação/tratamento farmacológico , Isoindóis/farmacologia , Isoquinolinas/farmacologia , Neuralgia/tratamento farmacológico , Ftalimidas/farmacologia , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Formaldeído/farmacologia , Adjuvante de Freund/farmacologia , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/métodos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacosRESUMO
Cytokine-induced neutrophil chemoattractant-1 (CINC-1), a member of the ELR+CXC subfamily [ELR motif (glutamic acid-leucine-arginine) adjacent to the cysteine-X-cysteine (CXC) motif located at the N-terminus of the protein], is an acute-phase protein and its synthesis is induced by endogenous and exogenous pyrogens. However, there are no studies on the pyrogenic property of CINC-1. Therefore, the present study evaluates whether centrally administered CINC-1 promotes an integrated febrile response along with an increase in the prostaglandin (PG)E2 content of the cerebrospinal fluid (CSF) of rats. The effects of antipyretic drugs on fever and on the PGE2 content of the CSF as well as the effectiveness of a neutralizing anti-CINC-1 antibody on the fever induced by CINC-1 have also been investigated. Intracerebroventricular (i.c.v.) injection of CINC-1 induced a dose-dependent bell-shaped rise on body temperature and increased PGE2 concentration in the CSF of conscious rats. Injected into the preoptic area of the anterior hypothalamus (AH/POA) (i.h.), CINC-1 also induced a dose-dependent bell-shaped increase in body temperature along with a decrease on tail skin temperature. Indomethacin (INDO, 2 mg kg(-1), i.p.) and ibuprofen (IBU, 10 mg kg(-1), i.p.) markedly reduced the fever evoked by i.c.v. injection of CINC-1 (25 ng/site). Orally given celecoxib (5 mg kg(-1), 30 min. before) abolished the fever induced by CINC-1 i.c.v. or i.h. (50 pg) injection. The antipyretic drugs also blocked the PGE(2) increase after CINC-1 i.c.v. injection. Co-injected anti-CINC antibody (10 ng/site) strongly reduced the febrile response induced by CINC-1 (50 pg/site) injected intrahypothalamically. This is the first time that centrally injected CINC-1 has been reported to act directly on the pyrogen-sensitive neurons of AH/POA, promoting a thermoregulatory response that seems to depend on other endogenous pyrogens synthesis and, as seen here, on PGE2.
Assuntos
Quimiocina CXCL1/fisiologia , Dinoprostona/líquido cefalorraquidiano , Febre/metabolismo , Área Pré-Óptica/metabolismo , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Temperatura Corporal/fisiologia , Celecoxib , Quimiocina CXCL1/administração & dosagem , Quimiocina CXCL1/efeitos dos fármacos , Relação Dose-Resposta a Droga , Febre/tratamento farmacológico , Injeções Intraventriculares , Masculino , Pirazóis/farmacologia , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Sulfonamidas/farmacologiaRESUMO
The present study investigated the role of kinins, prostaglandins (PGs) and nitric oxide (NO) in mechanical hypernociception, spontaneous nociception and paw oedema after intraplantar (ipl) injection of Tityus serrulatus venom (Tsv) in male Wistar rats. Tsv was ipl-injected in doses of 0.01-10microg/paw. Pre-treatment (30min prior) with DALBK (100nmol/paw) and icatibant (10nmol/paw), B1 and B2 selective kinin receptor antagonists, L-NAME (50mg/kg, i.p., a non-selective nitric oxide synthase inhibitor) or celecoxib, selective COX-2 inhibitor, was given 1h prior per os (5mg/kg, p.o.), significantly reduced the hypernociceptive response (Von Frey method), the spontaneous nociception (determined by counting the number of flinches) and paw oedema (plethysmometer method) induced by Tsv at doses of 1.0 and 10microg/paw for both nociceptive and oedematogenic responses, respectively. Nevertheless, indomethacin (5mg/kg, i.p., 30min prior) was ineffective in altering all of these events. The results of the present study show that Tsv, injected ipl into the rat paw, causes a dose-dependent paw oedema, mechanical hypernociception and flinches (a characteristic biphasic response) in which kinins and NO are substantially involved. Although celecoxib was effective against the oedema and pain caused by Tsv, COX-2 does not seem to be involved in the inflammatory response caused by Tsv.
Assuntos
Edema/induzido quimicamente , Cininas/fisiologia , Óxido Nítrico/fisiologia , Dor/induzido quimicamente , Prostaglandinas/fisiologia , Venenos de Escorpião/toxicidade , Animais , Edema/metabolismo , Eicosanoides/fisiologia , Injeções , Masculino , Dor/metabolismo , Ratos , Ratos Wistar , Venenos de Escorpião/administração & dosagem , Fatores de TempoRESUMO
Fever is considered an important component of the acute phase response of the body in defence against invading organisms such as bacteria. Quercetin, an important representative of the flavonoid class, has been extensively studied as an anti-inflammatory agent. In the present study, we investigated the effect of quercetin, administered orally (5, 25 and 50 mg kg(-1)) or intraperitoneally (50 mg kg(-1)), on the febrile response induced by either intraperitoneally (50 mug kg(-1)) or intravenously (5 mug kg(-1)) injected lipopolysaccharide (LPS from Escherichia coli) in rats. In contrast with the well known anti-inflammatory activity of quercetin, the results demonstrate that quercetin, at the doses used, did not alter the fever induced by LPS, regardless of the route of administration.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Febre/tratamento farmacológico , Quercetina/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Relação Dose-Resposta a Droga , Febre/induzido quimicamente , Injeções Intraperitoneais , Injeções Intravenosas , Lipopolissacarídeos/toxicidade , Masculino , Quercetina/administração & dosagem , Ratos , Ratos WistarRESUMO
Meloxicam (MLX) is an anti-inflammatory drug susceptible to variations and crystalline transitions. In compounding pharmacies, the complete crystallographic evaluation of the raw material is not a routine procedure. We performed a complete crystallographic characterization of aleatory raw MLX samples from compounding pharmacies. X-ray diffraction indicated the presence of two crystalline forms in one sample. DSC experiments suggested that crystallization, or a crystal transition, occurred differently between samples. The FTIR and 1H NMR spectra showed characteristic assignments. 13C solid-state NMR spectroscopy indicated the presence of more than one phase in a sample from pharmacy B. The Hirshfeld surface analysis, with electrostatic potential projection, allowed complete assignment of the UV spectra in ethanol solution. The polymorph I of meloxicam was more active than polymorph III in an experimental model of acute inflammation in mice. Our results highlighted the need for complete crystallographic characterization and the separation of freely used raw materials in compounding pharmacies, as a routine procedure, to ensure the desired dose/effect.
RESUMO
Recently, we demonstrated that nicorandil exhibits activities in models of inflammatory and nociceptive pain. In the present study, we extended this investigation by evaluating the effects of nicorandil in models of neuropathic pain induced by paclitaxel or nerve injury in mice. Four intraperitoneal (i.p.) injections of paclitaxel (2â¯mg/kg.day, cumulative dose 8â¯mg/kg) or chronic constriction injury (CCI) of the sciatic nerve induced a long lasting mechanical allodynia. Per os (p.o.) administration of two doses of nicorandil (50, 100 and 150â¯mg/kg) on the 14th day after the first paclitaxel injection attenuated the mechanical allodynia. Equimolar doses of nicotinamide (86.7â¯mg/kg, p.o.) or nicotinic acid (87.7â¯mg/kg, p.o.) were devoid of effect. Mechanical allodynia induced by CCI was also attenuated by p.o. administration of two doses of nicorandil (150â¯mg/kg) on the 14th day after nerve injury. Nicorandil (50, 100 and 150â¯mg/kg, p.o.) did not affect motor activity. The antinociceptive activity of nicorandil in the model of mechanical allodynia induced by paclitaxel was partially attenuated by naltrexone (5 and 10â¯mg/kg, i.p.) or cyproheptadine (5 and 10â¯mg/kg, i.p.), but not by glibenclamide (20 and 40â¯mg/kg, p.o.). Concluding, nicorandil exhibits activity in experimental models of neuropathic pain when mechanical allodynia is fully established. Activation of opioidergic and serotonergic pathways mediates the antinociceptive activity of nicorandil. It is unlikely that this activity requires biotransformation to nicotinamide or nicotinic acid. Nicorandil should be further evaluated aiming to identify a new alternative in the pharmacological management of neuropathic pain.