RESUMO
Pain is a usual and troublesome non-motor symptom of Parkinson's disease, with a prevalence of 29-82%. Therefore, it's vital to find pharmacological treatments for managing PD-associated pain symptoms, to improve patients' quality of life. For this reason, we tested the possible synergy between L-DOPA and celecoxib in decreasing allodynia and hyperalgesia induced by unilateral lesioning with 6-OHDA into the SNpc in rats. We also tested whether the antiallodynic and antihyperalgesic effect induced by combination of L-DOPA and celecoxib is mediated by the NO-cGMP-ATP-sensitive K+ channel pathway. Tactile allodynia and mechanical hyperalgesia were evaluated using von Frey filament. Isobolographic analyses were employed to define the nature of the drug interaction using a fixed dose ratio (0.5:â0.5). We found that acute and sub-acute (10-day) treatment with a single dose of L-DOPA (3-25 mg/kg, i. p.) or celecoxib (2.5-20 mg/kg, i. p.) induced a dose-dependent antiallodynic and antihyperalgesic effect in parkinsonian rats. Isobolographic analysis revealed that the ED50 values obtained by L-DOPA + celecoxib combination was significantly less than calculated additive values, indicating that co-administration of L-DOPA with celecoxib produces synergistic interactions in its antiallodynic and antihyperalgesic effect in animals with nigrostriatal lesions. Moreover, the antiallodynic and antihyperalgesic effects induced by L-DOPA + celecoxib combination were blocked by intrathecal pre-treatment with L-NAME, ODQ, and glibenclamide. Taken together, the data suggest that L-DOPA + celecoxib combination produces an antiallodynic and antihyperalgesic synergistic interaction at the systemic level, and these effects are mediated, at the central level, through activation of the NO-cGMP-ATP-sensitive K+ channel pathway.
Assuntos
Celecoxib/administração & dosagem , Hiperalgesia/metabolismo , Canais KATP/metabolismo , Levodopa/administração & dosagem , Óxido Nítrico/metabolismo , Transtornos Parkinsonianos/metabolismo , Animais , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Canais KATP/agonistas , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Ratos , Ratos WistarRESUMO
Preclinical Research & Development The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol-tapentadol combination in the formalin-induced pain model in mice. Paracetamol (56.23-562.3 mg/kg, i.p.) or tapentadol (1-10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose-response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1). Naloxone (1 and 5 mg/kg, i.p.), L-NAME (3 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.) were administered before the combination of drugs to evaluate the antinociceptive mechanisms of action. The results showed that the combination 1:1 and paracetamol3-tapenadol1 ratios produced additive effects, whereas the paracetamol1-tapentadol3 proportion showed an antinociceptive synergistic interaction. Moreover, naloxone and glibenclamide reversed the antinociceptive activity of the paracetamol-tapentadol mixture. Our results indicate that the paracetamol-tapentadol combination produces an antinociceptive synergistic interaction with the possible participation of ATP-sensitive K+ channels and µ-opioid receptors in the second phase of the formalin-induced pain model in mice.
Assuntos
Canais KATP/agonistas , Medição da Dor/métodos , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Tapentadol/administração & dosagem , Acetaminofen/administração & dosagem , Analgésicos não Narcóticos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Canais KATP/metabolismo , Masculino , Camundongos , Dor/induzido quimicamente , Dor/metabolismo , Receptores Opioides mu/metabolismoRESUMO
Over the last decade it has become evident that under normal conditions connexin hemichannels are either not expressed (e.g., skeletal muscle) or are expressed in very low numbers with low open probability in various mammalian tissues (e.g., liver and central nervous system (CNS)).[...].
Assuntos
Anti-Inflamatórios/uso terapêutico , Cálcio/metabolismo , Conexinas/genética , Inflamação/tratamento farmacológico , Canais KATP/genética , Trifosfato de Adenosina/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Cátions Bivalentes , Comunicação Celular/efeitos dos fármacos , Conexina 43/uso terapêutico , Conexinas/agonistas , Conexinas/metabolismo , Diazóxido/uso terapêutico , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Canais KATP/agonistas , Canais KATP/metabolismo , Aprendizado de Máquina , Fragmentos de Peptídeos/uso terapêutico , Transdução de SinaisRESUMO
The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE.
Assuntos
Sulfeto de Hidrogênio/agonistas , Óxido Nítrico/agonistas , Prunus avium/química , Triterpenos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Alcinos/antagonistas & inibidores , Alcinos/farmacologia , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , GMP Cíclico/metabolismo , Cistationina gama-Liase/química , Cistationina gama-Liase/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Frutas/química , Glibureto/antagonistas & inibidores , Glibureto/farmacologia , Glicina/análogos & derivados , Glicina/antagonistas & inibidores , Glicina/farmacologia , Sulfeto de Hidrogênio/metabolismo , Canais KATP/agonistas , Canais KATP/metabolismo , Masculino , Simulação de Acoplamento Molecular , NG-Nitroarginina Metil Éster/antagonistas & inibidores , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/química , Óxido Nítrico Sintase Tipo III/metabolismo , Extratos Vegetais/química , Ligação Proteica , Ratos , Triterpenos/isolamento & purificação , Vasodilatadores/isolamento & purificação , Ácido UrsólicoRESUMO
There is evidence that systemic sulfonylureas block diclofenac-induced antinociception in normal rat, suggesting that diclofenac activates ATP-sensitive K(+) channels. However, there is no evidence for the systemic interaction between different non-steroidal anti-inflammatory drugs (NSAIDs) and sulfonylureas in streptozotocin (STZ)-diabetic rats. Therefore, this work was undertaken to determine whether two sulfonylureas, glibenclamide and glipizide, have any effect on the systemic antinociception that is induced by diclofenac (30 mg/kg), lumiracoxib (56 mg/kg), meloxicam (30 mg/kg), metamizol (56 mg/kg) and indomethacin (30 mg/kg) using the non-diabetic and STZ-diabetic rat formalin test. Systemic injections of NSAIDs produced dose-dependent antinociception during the second phase of the test in both non-diabetic and STZ-diabetic rats. Systemic pretreatment with glibenclamide (10 mg/kg) and glipizide (10 mg/kg) blocked diclofenac-induced systemic antinociception in the second phase of the test (P<0.05) in both non-diabetic and STZ-diabetic rats. In contrast, pretreatment with glibenclamide or glipizide did not block lumiracoxib-, meloxicam-, metamizol-, and indomethacin-induced systemic antinociception (P>0.05) in both groups. Results showed that systemic NSAIDs are able to produce antinociception in STZ-diabetic rats. Likewise, data suggest that diclofenac, but not other NSAIDs, activated K(+) channels to induce its systemic antinociceptive effect in the non-diabetic and STZ-diabetic rat formalin test.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Canais KATP/agonistas , Canais KATP/fisiologia , Medição da Dor/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Diabetes Mellitus Experimental/metabolismo , Masculino , Medição da Dor/métodos , Ratos , Ratos WistarRESUMO
Despite the classical peripheral pronociceptive effect of noradrenaline (NA), recently studies showed the involvement of NA in antinociceptive effect under immune system interaction. In addition, the participation of the NO/cGMP/KATP pathway in the peripheral antinociception has been established by our group as the molecular mechanism of another adrenoceptor agonist xylazine. Thus the aim of this study was to obtain pharmacological evidences for the involvement of the NO/cGMP/KATP pathway in the peripheral antinociceptive effect induced by exogenous noradrenaline. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E(2) (2µg/paw). All drugs were locally administered into the right hind paw of male Wistar rats. NA (5, 20 and 80ng/paw) elicited a local inhibition of hyperalgesia. The non-selective NO synthase inhibitor l-NOarg (12, 18 and 24µg/paw) antagonized the antinociception effect induced by the highest dose of NA. The soluble guanylyl cyclase inhibitor ODQ (25, 50 and 100µg/paw) antagonized the NA-induced effect; and cGMP-phosphodiesterase inhibitor zaprinast (50µg/paw) potentiated the antinociceptive effect of NA low dose (5ng/paw). In addition, the local effect of NA was antagonized by a selective blocker of an ATP-sensitive K(+) channel, glibenclamide (20, 40 and 80µg/paw). On the other hand, the specifically voltage-dependent K(+) channel blocker, tetraethylammonium (30µg/paw), Ca(2+)-activated K(+) channel blockers of small and large conductance types dequalinium (50µg/paw) and paxilline (20µg/paw), respectively, were not able to block local antinociceptive effect of NA. The results provide evidences that NA probably induces peripheral antinociceptive effects by activation of the NO/cGMP/KATP pathway.
Assuntos
Analgésicos/farmacologia , GMP Cíclico/metabolismo , Canais KATP/agonistas , Canais KATP/metabolismo , Óxido Nítrico/metabolismo , Nociceptividade/efeitos dos fármacos , Norepinefrina/farmacologia , Análise de Variância , Animais , Pé/fisiologia , Masculino , Nociceptividade/fisiologia , Medição da Dor , Pressão , Ratos , Ratos WistarRESUMO
BACKGROUND: Propofol (2,6-diisopropylphenol) has been shown to protect several organs, including the kidneys, from ischemia-reperfusion (I-R)-induced injury. Although propofol affects adenosine triphosphate-sensitive potassium (K(ATP)) channels in nonrenal tissues, it is still not clear by which mechanisms propofol protects renal cells from such damage. In this study, we investigated whether propofol induces renal preconditioning through renal K(ATP) channels. METHODS: A reversible ATP depletion (antimycin A) followed by restoration of substrate supply in LLC-PK1 cells was used as an in vitro model of renal I-R. Cell viability was assessed by dimethylthiazol-diphenyltetrazol bromide and trypan blue dye exclusion test assays. Apoptosis was evaluated by annexin V-fluorescein isothiocyanate staining by flow cytometry and immunofluorescence. Propofol treatments were initiated at various time intervals: 1 or 24 h before ischemia, only during ischemia, or only during reperfusion. To evaluate the mechanisms of propofol protection, specific K(ATP) channel inhibitors or activators were used in some experiments during propofol pretreatment. RESULTS: Propofol attenuated I-R injury on LLC-PK1 cells when present either 1 or 24 h before initiated I-R, and also during the recovery period, but not when added only during ischemia. Propofol pretreatment significantly protected LLC-PK1 from I-R-induced apoptosis. The protective effect of propofol was prevented by glibenclamide (a sarcolemmal ATP-dependent K(+) channel blocker) and decreased by 5-hydroxidecanoic acid (a mitochondrial ATP-dependent K(+) channel blocker), but it was not modified by diazoxide (a selective opener of ATP-sensitive K(+) channel). CONCLUSION: Propofol protected cells against apoptosis induced by I-R. This protection was probably due to a preconditioning effect of propofol and was, at least in part, mediated by K(ATP) channels.
Assuntos
Canais KATP/agonistas , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Propofol/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Trifosfato de Adenosina/deficiência , Animais , Antimicina A/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoproteção , Ácidos Decanoicos/farmacologia , Diazóxido/farmacologia , Glibureto/farmacologia , Hidroxiácidos/farmacologia , Canais KATP/metabolismo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Células LLC-PK1 , Necrose , Bloqueadores dos Canais de Potássio/farmacologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Suínos , Fatores de TempoRESUMO
The mechanism by which yohimbine relaxes the human corpus cavernosum remains unclear. Using the human corpus cavernosum strips immersed in isometric baths containing Krebs-Henseleit solution, this study investigates the effect of yohimbine on the relaxation of the human corpus cavernosum through nitrergic pathways involving the activation of ATP-dependent potassium channels (K(ATP)). The maximal relaxation induced by yohimbine in the human corpus cavernosum strips pre-contracted with phenylephrine was 100+/-0% and only 30.5+/-5.0% when they were pre-contracted with 60-mM potassium (K(+)) solution. The maximal relaxation induced by yohimbine in phenylephrine pre-contracted tissues was significantly inhibited by tetrodotoxin, 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or 7-nitroindazole (43.6, 36.1 and 42.6%, respectively). Neither the combination charybdotoxin-apamin nor tetraethylammonium altered the response of the human corpora cavernosa strips to yohimbine. Nevertheless, glibenclamide decreased the maximum relaxant response to yohimbine by 29.8% (P<0.05; n=12). The results suggest that yohimbine relaxes the human corpus cavernosum by a non-adrenergic, non-cholinergic mechanism, probably activating the nitrergic-soluble guanylate cyclase (NO-sGc) pathway and K(ATP).