RESUMEN
Although the antinociceptive effects of N-palmitoyl-ethanolamine (PEA) were first characterized nearly 50 years ago, the identity of the mechanism that mediates these actions has not been elucidated. The present study investigated the contribution of K(+) channels on peripheral antinociception induced by the CB(2) agonist PEA. Nociceptive thresholds to mechanical paw stimulation of Wistar rats treated with intraplantar prostaglandin E(2) to induce hyperalgesia were measured, and other agents were also given by local injection. PEA (5, 10, and 20 µg/paw) elicited a local peripheral antinociceptive effect. This effect was antagonized by glibenclamide, a selective blocker of ATP-sensitive K(+) channels (20, 40, and 80 µg/paw). In addition, neither the voltage-dependent K(+) channel-specific blocker tetraethylammonium (30 µg/paw) nor the small and large conductance blockers of Ca(2+)-activated K(+) channels, dequalinium (50 µg/paw) and paxilline (20 µg/paw), respectively, were able to block the local antinociceptive effect of PEA. These results indicate that the activation of ATP-sensitive K(+) channels could be the mechanism that induces peripheral antinociception by PEA and that voltage-dependent K(+) channels and small and large conductance Ca(2+)-activated K(+) channels do not appear to be involved in this mechanism.
Asunto(s)
Analgésicos/farmacología , Hiperalgesia/tratamiento farmacológico , Canales KATP/efectos de los fármacos , Ácidos Palmíticos/farmacología , Amidas , Analgésicos/administración & dosificación , Animales , Decualinio/farmacología , Dinoprostona/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Endocannabinoides , Etanolaminas , Gliburida/administración & dosificación , Gliburida/farmacología , Hiperalgesia/fisiopatología , Indoles/farmacología , Canales KATP/metabolismo , Masculino , Ácidos Palmíticos/administración & dosificación , Ratas , Ratas WistarRESUMEN
The bisquinoline drug dequalinium (DQ) has demonstrated remarkable activity against some infection diseases, including malaria. Oxidative stress represents a biochemical target for potential antimalarials. In this work, we have tested the ability of this compound to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle, and dehydrogenase enzymes were investigated. The activity of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGLD) in infected cells were diminished by this drug compared to controls (300% and 80% approximately, respectively), while glutathione peroxidase (GPx), glutathione transferase (GST), and glutathione levels were also lowered. As a compensatory response, we could appreciate an increase of SOD activity (20% approximately) in infected cells treated with DQ; however, catalase was not affected by the compound. Lipid peroxidation was also decreased by this drug, protecting the cells from the hemolysis caused by the infection. In conclusion, oxidative stress represents a biochemical event which is modulated by DQ, interfering with the antioxidant regular activities in P. berghei infection.
Asunto(s)
Antiinfecciosos Locales/farmacología , Decualinio/farmacología , Eritrocitos/parasitología , Estrés Oxidativo , Plasmodium berghei/efectos de los fármacos , Animales , Catalasa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Transferasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Fosfogluconato Deshidrogenasa/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Bisquinoline compounds have exhibited remarkable activity in vitro and in vivo against Plasmodium parasites by inhibition of heme detoxification. We have tested the ability of dequalinium 1,1'-(1,10-decanediyl)bis(4-amino-2-methylquinoline), a known antimicrobial agent, to inhibit beta-hematin synthesis using a non-emzymatic colorimetric assay and globin proteolysis by electrophoretic analysis (SDS-PAGE-15%). Dequalinium was able to inhibit both processes in vitro with close correlation to a murine malaria model, reducing parasitemia levels, prolonging the survival time post-infection and curing 40% of infected mice using a combination therapy with a loading dose of chloroquine. These results confirm that dequalinium is a promising lead for antimalarial drug development.
Asunto(s)
Antiinfecciosos/farmacología , Decualinio/farmacología , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Animales , Antiinfecciosos/uso terapéutico , Colorimetría , Decualinio/uso terapéutico , Modelos Animales de Enfermedad , Electroforesis en Gel de Poliacrilamida , Globinas/efectos de los fármacos , Globinas/metabolismo , Hemoproteínas/biosíntesis , Hemoproteínas/efectos de los fármacos , Malaria/parasitología , Masculino , Ratones , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Plasmodium berghei/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Central anti-nociceptive actions of baclofen involve activation of K+ channels. Here we assessed what types of K+ channel might participate in the peripheral anti-nociception induced by baclofen. EXPERIMENTAL APPROACH: Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E2.(PGE2) to induce hyperalgesia were measured 3 h after PGE2 injection. Other agents were also given by intraplantar injection. KEY RESULTS: Baclofen elicited a dose-dependent (15 - 240 microg per paw) anti-nociceptive effect. An intermediate dose of baclofen (60 microg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABAB receptor antagonist saclofen (12.5 - 100 microg per paw) antagonized, in a dose-dependent manner, peripheral antinociception induced by baclofen (60 microg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABAA receptor antagonist (80 microg per paw), or by (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid, GABAC receptor antagonist (20 microg per paw). The peripheral antinociception induced by baclofen (60 microg) was reversed, in a dose-dependent manner, by the voltage-dependent K+ channel blockers tetraethylammonium (7.5 - 30 microg per paw) and 4-aminopyridine (2.5 - 10 microg per paw). The blockers of other K+ channels, glibenclamide (160 microg), tolbutamide (320 microg), charybdotoxin (2 microg), dequalinium (50 microg) and caesium (500 microg) had no effect. CONCLUSIONS AND IMPLICATIONS: This study provides evidence that the peripheral antinociceptive effect of the GABAB receptor agonist baclofen results from the activation of tetraethylammonium-sensitive K+ channels. Other K+ channels appear not to be involved.
Asunto(s)
Analgésicos/farmacología , Baclofeno/farmacología , Agonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Canales de Potasio/efectos de los fármacos , Tetraetilamonio/farmacología , Animales , Baclofeno/análogos & derivados , Bicuculina/farmacología , Cesio/farmacología , Caribdotoxina/farmacología , Decualinio/farmacología , Gliburida/farmacología , Masculino , Ratas , Ratas Wistar , Tolbutamida/farmacologíaRESUMEN
The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K(+) channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous micro-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. In the current study, we assessed whether bremazocine is capable to activate K(+) channels eliciting antinociception. Bremazocine (20, 40 and 50 microg) dose-dependently reversed the hyperalgesia induced in the rat paw by local injection of carrageenan (250 microg) or prostaglandin E(2) (2 microg), measured by the paw pressure test. Using the selective kappa-opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 200 microg/paw), it was confirmed that bremazocine (50 microg/paw) acts specifically on the kappa-opioid receptors present at peripheral sites. Prior treatment with the ATP-sensitive K(+) channel blockers glibenclamide (40, 80 and 160 microg) and tolbutamide (40, 80 and 160 microg) did not antagonise the antinociceptive effect of bremazocine (50 microg). The same results were obtained when we used prostaglandin E(2) (2 microg) as the hyperalgesic stimulus. The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers dequalinium (12.5, 25 and 50 microg) and charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers tetraethylammonium (25, 50 and 100 microg) and 4-aminopyridine (10, 25 and 50 microg). None of the K(+) channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation.
Asunto(s)
Analgésicos/farmacología , Benzomorfanos/farmacología , Naltrexona/análogos & derivados , Sistema Nervioso Periférico/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Receptores Opioides kappa/agonistas , 4-Aminopiridina/farmacología , Transportadoras de Casetes de Unión a ATP , Analgésicos/antagonistas & inhibidores , Animales , Benzomorfanos/antagonistas & inhibidores , Caribdotoxina/farmacología , GMP Cíclico/fisiología , Decualinio/farmacología , Gliburida/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Canales KATP , Masculino , Naltrexona/farmacología , Óxido Nítrico/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Tetraetilamonio/farmacología , Tolbutamida/farmacologíaRESUMEN
A comparative analysis of the in vitro quelating effect of Endodent, Largal Ultra and Salvident was done evaluating the decrease of dentine weight that they produced. The samples of dentine, each time included in the same volume of the three agents during 24 and 48 hours. Largal Ultra was in the 100% of the cases, the quelating that more decrease of weight produced.