RESUMO
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
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
Serotonin (5-HT) acts as a neurotransmitter in the central nervous system (CNS) and as a mediator released by enterochromaffin cells to regulate intestinal motility. However, this amine also plays an important role as an inflammatory mediator and induces phenotypic changes of nociceptors. Despite the wide knowledge of the role of 5-HT in nociception, most studies have focused on its role in the CNS, while a clear information about its role in peripheral tissues is still lacking. In the present study, we investigated the role of peripheral 5-HT receptors in the nociceptive response induced by 5-HT or carrageenan in mice by using antagonists that target different 5-HT receptors. Mechanical nociceptive threshold was measured with an analgesimeter and evaluated after intraplantar (i.pl.) injection of 5-HT or carrageenan. 5-HT antagonists were injected via the i.pl. route. 5-HT (10, 20, 40 or 80 µg/paw) or carrageenan (100 µg/paw) induced mechanical allodynia. Pretreatment with isamoltane (5 µg; 5-HT1B antagonist) or ketanserine (1 µg; 5-HT2A antagonist) did not affect the mechanical allodynia induced by 5-HT. This response was inhibited by BRL 15572 (10 µg; 5-HT1D antagonist) or SB 269970 (25 µg; 5-HT7 antagonist). On the other hand, mechanical allodynia induced by 5-HT or carrageenan was exacerbated by ondansetron (10, 20 or 40 µg; 5-HT3 antagonist). The results indicate that activation of 5-HT1D and 5-HT7 receptors plays a role in the mechanical allodynia induced by 5-HT in mice. This study also demonstrates the inhibitory role of peripheral 5-HT3 receptors in the nociceptive response induced by 5-HT or carrageenan.
Assuntos
Hiperalgesia/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Animais , Carragenina , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Nociceptividade , Ondansetron/farmacologia , Limiar da Dor , Serotonina , Antagonistas da Serotonina/farmacologia , Transdução de SinaisRESUMO
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
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
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.
Assuntos
Analgésicos/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Nicorandil/farmacologia , Peptídeos Opioides/metabolismo , Paclitaxel/efeitos adversos , Serotonina/metabolismo , Analgésicos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Nicorandil/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesõesRESUMO
We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300µg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity.
Assuntos
Analgésicos/metabolismo , Analgésicos/farmacologia , Nicorandil/metabolismo , Nicorandil/farmacologia , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/patologia , Transdução de Sinais/efeitos dos fármacos , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Nicorandil/uso terapêuticoRESUMO
The research on sex differences in nociception and antinociception as well as sex and gender differences in pain and analgesia is a maturing field. There is a vast literature showing experimental and clinical pain suppressive effects induced by minocycline, especially in inflammatory pain. However, as far as we know, possible qualitative or quantitative sex differences in those effects remained to be examined. By employing the formalin test, which has two phases of experimental pain behavior that models nociceptive pain (i.e., first phase) and inflammatory pain (i.e., second phase), we initially evaluated the effect induced by minocycline in female or male C57BL/6 mice. The treatment reduced the second phase of licking behavior in both females and males, and the effects were quantitatively similar in both sexes. Likewise, the same sex-independent effect was observed in Swiss mice, suggesting a genotype-unspecific sex-independent effect. While minocycline is already being tested in clinical trials, this appears to be the first preclinical investigation of sex differences in the experimental pain suppressive effects induced by this widely studied drug. The independence of sex in the antinociceptive effect induced by minocycline may be hopefully translated to gender-independent analgesic effects, which would be surely promising in a therapeutic paradigm.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Minociclina/uso terapêutico , Dor/tratamento farmacológico , Animais , Feminino , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Dor/fisiopatologia , Fatores Sexuais , Especificidade da EspécieRESUMO
Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 µg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.