Participation of the NO/cGMP/K+ATP pathway in the antinociception induced by Walker tumor bearing in rats

Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K+ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K+ATP pathway in antinociception induced in Walker 256 tumor-bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E2- (PGE2, 400 ng/paw; 50 µL; intraplantar injection) and carrageenan-induced hypernociception (500 µg/paw; 100 µL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE2) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE2) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE2; 8 µg/paw) and the ATP-sensitive K+ channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE2; 160 µg/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels.

Differential inhibitory potencies of alcoholic extract of different parts of Dryopteris chrysocoma on inflammation in mice and rats

Phytomedicinal therapy for inflammation is not new and it is highly effective for the treatment of various inflammatory disorders. The inflammation is one of the initial parameter for most of the disorders occurring in the body. The anti-inflammatory potential can be determined by using various techniques. Dryopteris chrysocoma is a male fern commonly found in damp and moist areas of Pakistan. The study was conducted on mice and rats by inducing inflammation with subcutaneous administration of formalin and Carrageenan in hind paw. The results were compared with standard drug Aspirin administered orally in the dose of 300 mg/kg and a decrease in hind paw volume was observed. The intensity of edema was observed in mice after formalin injection and the time of disappearance of edema was observed. In rats the inhibition of inflammation by root, leaves and stem extract was 51.19%, 41.66% and 30.95% respectively after administration of formalin. Similar inhibition of inflammation produced by root, leaves and stem extracts i.e. 57%, 42% and 35% respectively in Carrageenan treated rats. Root extract showed the highly significant results at p

Polyamines in inflammation and their modulation by conventional anti-inflammatory drugs.

Significant increase in polyamines levels in inflamed tissue was observed in the experimental animal models of inflammation. Treatment with dexamethasone positively modulated the levels of polyamines whereas non-steroidal drugs, diclofenac and valdecoxib negatively modulated their levels.

Cholinergic-NO-cGMP mediation of sildenafil-induced antinociception.

Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.

Estudo da açäo antiinflamatória e potência ulcerogênica de compostos mesoiônicos, 1,4-difeniltiossemicarbazida e derivados / Study of the antiinflammatory action and ulcerogenic potency of mesoionics, 1,4-diphenylthiosemicarbazide compounds and derivatives

Os compostos 1,4-difeniltiossemicarbazida (DTSC), derivados (`IR IND. 1ï; `IR IND. 2ï e `IR IND. 3ï) e mesoiônicos (`MIR IND. 1ï, `RMIR IND. 1ï e `RMIR IND. 3ï) foram avaliados quanto à atividade antiinflamatória. os compostos DTSC, `IR IND. 1ï, `IR IND. 2ï, e `RMIR IND. 1ï inibiram significativamente o pico máximo do edema induzido por carragenina em 82 por cento, 72 por cento, 34 por cento e 78 por cento, respectivamente. Porém, somente os derivados mesoiônicos inibiram o edema induzido por dextrano. Já no edema desencadeado por histamina, somente o composto IR, não foi capaz de antagonizar de maneira significativa a ação da histamina...

Efecto de la carragenina e indometacina sobre el crecimiento de un fibrosarcoma murino / Effect of carrageena and indomethacin on the growth of a murine fibrosarcoma

Los tumores sólidos para crecer más de 2 mm, necesitan desarrollar nuevos vasos sanguíneos. Las células neoplásicas secretan factores de crecimiento que estimulan la angiogénesis y el crecimiento tumoral. La Carragenina bloquea un vitro la unión de los factores de crecimiento a sus receptores. Ensayamos in vivo su acción con el objetivo de analizar si inhibe el desarrollo de un fibrosarcoma murino. Para neutralizar la acción inflamatoria de la Carragenina usamos la Indometacina, que es un antiinflamatorio no esteroide. El tumor usado fue en fibrosarcoma inducido con metilcolanterno en ratones Balb/c y mantenido por pasaje seriado de células tumorales, en ratones de la misma cepa. El volumen de los tumores fue evaluado midiendo dos dimensiones y aplicando la fórmula V = 0.4 x d(2) x D. Los ratones con tumores fueron separados en grupos, uno de los cuales se usó como testigo y los otros tratados en forma separada con indometacina, Carragenina y Carragenina-Indometacina. Se comparó el volumen de los tumores de los ratones tratados con respecto al testigo y el de los tratados entre sí, utilizando el Test t de Student. Se demostró que la Carregenina y la indometacina, inhiben el desarrollo del fibrosarcoma. La acción inhibitoria de la Carragenina sobre el crecimiento tumoral es significativamente mayor que el efecto antitumoral de la Indometacina y el de la Corragenina-Indometacina.

Effects of high doses of diazepam on carrageenin-induced paw edema in rats

Benzodiazepine (BDZ) receptor sites play a relevant role in immune/ inflammatory reactions. Acute BDZ treatments were shown not only to suppress cell proliferation in rat thymus but also to decrease TNF-alpha, IL-1 and IL-6 release from adult mouse macrophages. In the present investigation the effects of acute (l0.0 and 20.0 mg/kg) and long-term (10.0 mg kg(-1) day(-l), for 21 days) diazepam treatment on carrageenin-induced paw edema were studied in rats. The results showed that acute treatment with high doses of diazepam decreased paw edema volume in a dose-dependent manner, and this effect was observed as early as 1 h after the administration of the 20.0 mg/kg dose and continued until the last measurement was performed (8 h). In contrast, long-term diazepam administration did not modify the phlogistic-induced edema. Taken together, these data show that 1) acute diazepam treatment with high doses decreases the volume of the acute inflammatory paw edema developed by the organism as a response to carrageenininduced injury, and 2) long-term diazepam treatment induces tolerance to this effect. These results are discussed in the light of a possible effect of diazepam on the components of the rat cellular and humoral immune/inflammatory reaction such as T lymphocytes and/or interleukins.

IDPH-8261--a new nonsteroidal antiinflammatory agent.

IDPH-8261, methyl alpha-methyl-4-(3-thienyl)benzeneacetate, exhibited marked anti-inflammatory activity in acute, subacute and chronic models of inflammation. In rats, IDPH-8261 exhibited a dose related inhibition of carrageenin-induced rat paw edema and the inhibition was greater than ibuprofen, phenylbutazone, but was three times less than indomethacin. It exhibited anti-inflammatory activity in normal and adrenalectomized rats. It also exhibited the activity against various phlogistic agents. IDPH-8261 exhibited AI activity in subacute granuloma tests. In adjuvant-induced established polyarthritis. IDPH-8261 exhibited anti-arthritic effect at a very low dose (ED50 = 4 mg/kg, p.o.). Ulcerogenic liability was the lowest (UD50 = 180 mg/kg, p.o.), when compared to reference standard drugs. Low toxicity and high efficacy may make this compound a potentially useful therapeutic agent.

Pertussis toxin from Bordetella pertussis blocks neutrophil migration and neutrophil-dependent edema in response to inflammation

Pertussis toxin (Ptx) is a hexameric protein with classical AB architecture produced by Bordetella pertussis. The aim of this study was to investigate the effect og Ptx on migration of polymorphonuclear leukocytes to site of inflamation and on cell- dependent edema. Ptx was purified from the supernatant of the culture medium of B. pertussis using hydroxylapatite chromatography and fetuin affinity chromatography. Ptx induced a maximal clusterin of Chinese hamster ovary cells at concentration as low as 0.1 ng/ ml. Intravenous inection of Ptx (400 ng) significantly blocked the neutrophil migration induced by 200 ng of lipopolysaccharide (LPS from E. coli O111:B4; 2.27 ñ 0.13 vs 0.61 ñ 0.16 per 10**6 neutrophils/ml; P < 0.001; N = 5) and by 200 ng of formylmethionyl-leucyl-phenylalanine(fMLP; 2.53 ñ 0.45 vs 0.75 ñ 0.14 per 10**6 neutrophils/ml; P < 0.01; N=6) into the peritoneal cavities of male Wistar rats (eighing 150-180). In addition, Ptx (400ng) pretreatment also blocked the edema induced by intraplantar injection of 100 µg carrageenin ( increase in volume: 0.667 ñ 0.087 vs 0.313 ñ 0.058 ml; P < 0.01; N = 5) but not the edema induced by 100 µg dextran ( increase in volume: 0.537 ñ 0.06 vs 0.385 ñ 0.076 ml; P > 0.05; N = 5). These data demonstrate that Ptx blocked neutrophil migration induced by a direct f MLP stimulus of a site of inflammation. In addition, this toxin blocks the indirect stimulus of LPS on neutrophil migration. Furthermore, Ptx also inhibits the neutrophil-dependent edema induced by carrageenin, but not the edema induced by dextran that is in part dependent on basophil cells. These results warrant further studies on the mechanisms of Ptx inhibition of neutrophil-dependent edema and cell migration

Participation of macrophages in chloramphenicol-potentiated carrageenin-induced peritonitis in rats

1. We investigated the possible potentiating effect of chloramphenicol succinate (30 mg/kg, every 12 h for 4 days, ip) on the response of polymorphonuclear neutrophils to carrageenin (150 micrograms, ip) or dextran (100 micrograms, ip) in the peritoneal cavity of male Wistar rats (180-230 g; N = 12 in each group). 2. Chloramphenicol potentiated the cell migration induced by carrageenin (35 per cent ) but not that induced by dextran. Previous macrophage depletion in the peritoneal cavity by washing with sterile saline abolished the cell response, whereas a previous thioglycollate-induced increase in macrophage numbers enhanced the potentiating effect (60 per cent ). 3. These results suggest that the potentiating effect on polymorphonuclear neutrophil migration induced by chloramphenicol may be related to chemotactic factors released by macrophages

Efeitos da indometacina na inflamaçäo induzida em ratos / Effects of indomethacin over the experimental inflammation in rats

O objetivo desta pesquisa foi quantificar a amplitude de açao, em ratos, de droga antiinflamatória nao esteróide (indometacina), largamente utilizada em cirurgia. Em ensaios clínicos há dificuldade de se quantificar essa açao em termos numéricos, sobre os quais possam ser aplicados testes estatísticos de alto poder de prova. Nesta pesquisa o efeito da indometacina foi quantificado no edema da pata de ratos induzido por carregenia, na pleurisia por carragenina, na inflamaçao crônica por pelotas de algodao implantadas na parede abdominal e no glanuloma de corpo estranho induzido por fio de polipropileno implantado no dorso. Constatou-se que a indometacina reduziu o edema da pata dos ratos tratados para 51 por cento do edema em relaçao ao grupo-controle, o volume do exsudato pleural para 50 por cento, o número de células da pleurisia para 58 por cento e o peso seco do material inflamatório no abdome para 64 por cento. No granuloma induzido no dorso, a indometacina diminuiu o número de neutrófilos para 28 por cento, de macrófagos para 55 por cento, de fibroblastos para 66 por cento e de fibras colágenas para 75 por cento. Concluiu-se que a indometacina reduz siginificativamente a amplitude da inflamaçao aguda e crônica e deve ocupar lugar de destaque no arsenal terapêutico do cirurgiao, atuando na prevençao e no tratamento dos efeitos nicovos da inflamaçao.

Efeitos da ofloxacina na inflamaçäo induzida em ratos / Effects of ofloxacin over the induced inflammation in rats

O objetivo desta pesquisa foi investigar a eventual açao antiinflamatória do antibiótico ofloxacina, em ratos. O efeito da ofloxacina foi pesquisado no edema experimental de pata por carragenina e por dextrana, na pleurisia por carragenina, na inflamaçao crônica por pelotas de algodao implantadas na parede abdominal e no granuloma de corpo estranho por fio de polipropileno implantado no dorso. Costatou-se que a ofloxacina nao influenciou a evoluçao da inflamaçao, exceto por inibir (em altas doses) a proliferaçao de células inflamatórias mononucleares do granuloma de corpo estranho formado pela presença de fio de polipropileno. Concluiu-se que a ofloxacina tem açao antiproliferativa sobre células inflamatórias de ratos.

Inflammatory response modulated by pinealectomy: effect of light

In view nof the known interactions between pineal and adrenal glands and the importance of glucocorticoids on the acute phase of the inflammatory process, we investigated the effect of the pineal gland on the paw edema response induced by carrageenin in female Wistar rats, weighing 170-220 g, measured by the pletysmographic method. Adrenalectomy increased the rate of the inflammatory response (149.02 ñ 2.93%, N=7 vs 113.48 ñ 2.99%, N=7) whereas pinealectomy and sham-pinealectomy under white light had an inhibitory effect (81.73 ñ 2.16%, N=15 and 80.21 ñ 1.85%, N=14 vs 113.48 ñ 2.99%, N=7). Sham-pinealectomy under red light did not modify the rate of the inflammatory response. These results indicate that the pineal gland can be affected by light during sham-pinealectomy. In view of the unaltered adrenal gland weight and corticosterone levels among the different groups, we propose an antagonism between melatonin (pineal hormone) and glucocorticoids at the peripheral level. The predominant effect of glucocorticoids over melatonin may explain the inhibition of the inflammatory response caused by pinealectomy

PAF-acether and the acute inflammatory reaction

PAF-aceter é um fosfolipídio que exerce um papel importante na reaçäo inflamatória aguda. No modelo experimental do edema da para de rato e pleurisia, a reaçäo induzida pelo PAF era acompanhada de hemoconcentraçäo, embora esses processos pareçam ser mediados por mecanismos distintos. Antagonistas específicos do PAF, como BN 52021 e WEB 2086, inibem 60% do edema induzido pelo PAF. Leucotrienos e mecanismos histaminérgicos envolvendo receptores H2 parecem participar no processo. A participaçäo do sistema adrenérgico e de metabólitos da ciclooxigenase é controversa. Infiltraçäo de leucócitos, observada após a injeçäo de PAF, e plaquetas näo säo necessárias para a formaçäo de edema. Auto-dessensibilizaçäo induzida pelo PAF pôde ser observada, sendo seletiva e dependente a interaçäo do PAF com receptores específicos em um processo de regulaçäo depressiva ("dow-regulation"). Nenhuma participaçäo deo PAF foi observada na reaçäo inflamatória induzida pela carregenina, contrariamente áquela provocada pelo zimosan, que é principalmente dependente do PAF-aceter

Strain dependent & selective modulation of murine humoral immune response by carrageenan.

Carrageenan (CGN), a polygalactan extracted from red algae, induced 90 per cent suppression of antibody response to sheep red blood cells in Balb/C strain as compared to the untreated controls. Whereas the treatment failed to induce suppression in C57BL/6 strain. The observed suppression of antibody response was significant on all days tested (up to 40 days) and the suppression induced by CGN was real and not due to any direct effect on antigen or on the assay system followed. On the other hand, as evident from foot-pad thickness, the delayed type hypersensitivity (DTH) was unaltered in Balb/C strain after CGN treatment.

Do lymphocytes play a pro-inflammatory role in any pharmacological type of rat paw edema?

1. The hypothesis of a pro-inflammatory activity in lymphocytes related to the development of nonimmune acute inflammation was tested in leucopenic rats injected subcutaneously with various stimuli representing different pharmacological classes of paw edema-inducing agents into the subplantar area of one of the hind paws. 2. Amethopterin-induced leucopenia rendered animals hyporeactive to carrageenin and trypsin, but not to kaolin or dextran. 3. Administration of splenic lymphocytes to leucopenic rats to correct lymphopenia partially restored the inhibited responses to carrageenin and the early phase of responses to trypsin. 4. These results suggest that lymphocytes may play a pro-inflammatory role in nonimmune acute inflammation, with is more demonstrable in some pharmacological classes of paw edema than in others

Effect of iv administered hyperosmotic sodium chloride on carrageenan-induced pleurisy in adrenalectomized and intact rats

The effect of administration of hyperosmotic NaCl (2ml, 7.8% NaCl, iv) on carregeenan induced pleurism was determined in adrenalectomized and intact rats. tThe volume of the pleural exudate was significantly reduced 4 h after induction by treatment with hyperosmotic NaCl for both adrenalectomized (0.08 - 0.16 ml) and intact (0.03 - 0.08 ml) animals compared to their untreated controls (0.56 - 0.44 ml and 0.26 - 0.15 ml, respectively). Similarly, hyperosmotic NaCl treatment significantly reduced the total number of inflammatory cells in the pleural cavity: 29.60 x 10**6 cells for adrenalectomized animlas and 28.90 x 10**6 ñ 11.43 x 10**6 cells for intact animals compared to 63.67 x 10**6 cells for their untreated controls. Tretament with isotonic saline did not affect carrageenan-induced pleurisy. These data suggest that chemical mediator(s) of inflammation may be involved in the mechanism(s) of action of a hyperosmotic NaCl solution on the acute inflammatory response

Inflammatory edema induced by carrageenin in monosodium glutamate-treated rats

Rats treated with monosodium glutamate (MSG) during the neonatal period show hypothalamic lesions and multiple neuroendocrine alterations manifested as a remarkable increase in levels of circulating corticosterone and obesity. Paw edema induced by local injection of carrageenin was significantly reduced in MSG-treated rats compared to normal rats. In contrast, both adrenalectomized rats and adrenalectomized, MSG-treated rats showed an increased response to carrageenin relative to controls. These results suggest that glucocorticoids are important modulators of inflammation in this phase of the process