Therapeutic effect of resveratrol on morphine-induced damage in male reproductive system of mice by reducing nitric oxide serum level / Efecto terapéutico de resveratrol sobre el daño inducido por la morfina en el sistema reproductor masculino de ratones reduciendo el nivel de óxido nítrico del suero

SUMMARY: Morphine is one of the naturally occurring phenanthrene alkaloids of opium that induces adverse effects on male reproductive system. Resveratrol is a phytoestrogen and antioxidant of red grape. The main goal is to investigate whether resveratrol could inhibit adverse effects of morphine on sperm cell viability, count, motility as well as testis histology, testosterone hormone and nitric oxide levels in mice. In the present study, 48 male rats were randomly divided into 8 groups (n=6) and were treated intraperitoneally for 14 days with normal saline, resveratrol (2, 8, 20 mg/kg/day), morphine (20 mg/kg/day) and morphine (20 mg/kg/day) + resveratrol (2, 8, 20 mg/kg/day). At the end of experiments, sperm parameters (sperm cell viability, count, motility and morphology), testis weight, the diameter of seminiferous tubules, testosterone hormone level and nitric oxide were analyzed. The data were analyzed by SPSS software for windows (version 20) using one-way ANOVA test followed by Tukey's post hoc test, and P<0.05 was considered significant. The results indicated that morphine administration significantly decreased testosterone level, count, viability and motility of sperm cells and testis weight and increased nitric oxide compared to the saline group (P=0.000). Administration of resveratrol and resveratrol plus morphine significantly increased motility, count and viability of sperm cells, somniferous tubule diameter and testosterone, while it decreased nitric oxide level compared to morphine group (P=0.025). It seems that resveratrol administration could increase the quality of spermatozoa and prevented morphine-induced adverse effects on sperm parameters.

RESUMEN: La morfina es uno de los alcaloides fenantreno del opio que induce efectos adversos en el sistema reproductivo masculino. El resveratrol es un fitoestrógeno y antioxidante de la uva roja. El objetivo principal de este trabajo fue investigar si el resveratrol puede inhibir los efectos adversos de la morfina sobre la viabilidad celular de los espermatozoides, el recuento y la motilidad, así como la histología de los testículos, la hormona testosterona y los niveles de óxido nítrico en ratones. Se dividieron, aleatoriamente, 48 ratas machos en 8 grupos (n = 6) y se trataron de forma intraperitoneal durante 14 días con solución salina normal, resveratrol (2, 8, 20 mg / kg / día), morfina (20 mg / kg / día ) y morfina (20 mg / kg / día) + resveratrol (2, 8, 20 mg / kg / día). Al final de los experimentos, se analizaron los parámetros espermáticos (viabilidad celular, recuento, motilidad y morfología), el peso de los testículos, el diámetro de los túbulos seminíferos, el nivel de la hormona testosterona y el óxido nítrico. Los datos fueron analizados con el software de SPSS para Windows (versión 20) usando una prueba de ANOVA de una vía seguida de la prueba post hoc de Tukey, y P <0,05 se consideró significativo. Los resultados indicaron que la administración de morfina disminuyó significativamente el nivel de testosterona, el recuento, la viabilidad y la motilidad de los espermatozoides y el peso de los testículos, además del aumento de óxido nítrico en comparación con el grupo salino (p = 0,000). La administración de resveratrol y resveratrol más morfina aumentó significativamente la motilidad, el recuento y la viabilidad de los espermatozoides, el diámetro de los túbulos seminíferos y la testosterona, mientras que disminuyó el nivel de óxido nítrico comparado con el grupo morfina (p = 0,025). En conclusión, la administración de resveratrol podría aumentar la calidad de los espermatozoides y prevenir los efectos adversos inducidos por la morfina sobre los parámetros espermáticos.

Protective effect of resveratrol against morphine damage to kidneys of mice / Efecto protector de resveratrol contra el daño de la morfina en riñones de ratones

SUMMARY: Morphine produces free radicals and cause apoptosis in some cell. Resveratrol (RSV) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury. 48 male mice were randomly assigned to 8 groups. In this study, various doses of RSV (2, 8 and 20 mg/kg) and RSV plus Morphine (2, 8 and 20 mg/kg) were administered intraperitoneally to male mice for 20 consequent days and weight of kidneys, biochemical characteristics, morphometric markers and blood serum nitric oxide level were studied. The results indicated that morphine administration significantly increased the mean diameter of glomerulus and distal and proximal convoluted tubule, Lactate dehydrogenase (LDH), Blood urea nitrogen (BUN), creatinine and nitric oxide levels compared to the saline group (P<0.05). However, RSV and RSV plus morphine in all doses significantly decreased glomeruli number and LDH, BUN, creatinine and nitric oxide levels compared to morphine groups (p<0.05). Thus, it seems that resveratrol improved kidney damages induced by morphine in mice.

RESUMEN: La morfina produce radicales libres y causa apoptosis en algunas células. El resveratrol (RSV) es un tipo de fenol natural y una fitoalexina producida por varias plantas en respuesta a una lesión. Se asignaron al azar 48 ratones machos a 8 grupos. En este estudio se administraron varias dosis de RSV (2, 8 y 20 mg/kg) y RSV más morfina (2, 8 y 20 mg/kg) intraperitoneal en ratones machos durante 20 días consecutivos y se estudió el peso de los riñones, las características bioquímicas, los marcadores morfométricos y el nivel de óxido nítrico en suero sanguíneo. Los resultados indicaron que la administración de morfina aumentó significativamente el diámetro medio del glomérulo y de los túbulos distal y proximal, los niveles de lactato deshidrogenasa (LDH), nitrógeno ureico en sangre (BUN), la creatinina y el óxido nítrico en comparación con el grupo salino (p <0,05). Sin embargo, el RSV y el RSV más morfina en todas las dosis redujeron significativamente el número de glomérulos y LDH, BUN, la creatinina y el óxido nítrico en comparación con los grupos de morfina (p <0,05). Por lo tanto, los resultados podrían indicar que el resveratrol mejoró el daño renal inducido por la morfina en ratones.

Morphine does no promote esophageal carcinogenesis in rats exposed to diethylnitrosamine

BACKGROUND: The high incidence of esophageal cancer in the north of Iran has been associated to the consumption of opium and exposure to nitrosamines. Diethylnitrosamine has an established potential of producing experimental cancer in the esophagus and liver. AIM: To evaluate by histopathology the effect of oral administration of morphine and diethylnitrosamine during 23 weeks on the hepatic and esophageal carcinogenesis on 176 rats. METHODS: We divided the rats into the following groups: Morph: morphine; Den: diethylnitrosamine; Den+morph: Den and morphine in the same solution; Den/morph: Den and morphine in different solutions and days. RESULTS: Morphine did not promote neoplasias. The highest neoplastic incidents were found: a) in the esophagus, Den in relation to Den/morph and Den+morph (71.1 percent, 55.8 percent, and 50.0 percent); b) in the liver, Den and Den/morph in relation to Den+morph (73.8 percent, 81.4 percent, and 40.9 percent); c) higher incident of hepatic neoplasia than esophageal in Den/morph (81.4 percent and 55.8 percent). Different doses of diethylnitrosamine were ingested among the groups Den, Den/morph, and Den+morph, respectively 2.9, 2.8, and 2.3 mg/kg/day. CONCLUSIONS: These results show that the morphine did not promote esophageal carcinogenesis and may have stimulated the hepatic metabolism of the first pass of the carcinogen.

RACIONAL: A alta incidência de câncer esofagiano no norte do Irã foi associada ao consumo de ópio e exposição às nitrosaminas. A dietilnitrosamina possui potencial estabelecido de produzir câncer experimental em esôfago e fígado. OBJETIVO: Avaliar por histopatologia o efeito da administração oral de morfina e de dietilnitrosamina na carcinogênese esofágica e hepática em ratos. MÉTODOS: Durante 23 semanas, 176 ratos ingeriram diferentes soluções, sendo divididos em grupos: Morf: morfina; Den: dietilnitrosamina; Den+morf: dietilnitrosamina e morfina numa mesma solução; Den/morf: dietilnitrosamina e morfina em diferentes soluções e dias. RESULTADOS: Morf não promoveu neoplasias. Encontraram-se maiores incidências neoplásicas: a) no esôfago, Den em relação à Den/morf e Den+morf (71,1 por cento, 55,8 por cento e 50,0 por cento); b) no fígado, Den e Den/morf em relação à Den+morf (73,8 por cento, 81,4 por cento e 40,9 por cento); c) maior incidência de neoplasia hepática do que esofágica em Den/morf (81,4 por cento e 55,8 por cento). Diferentes doses de dietilnitrosamina foram ingeridas entre os grupos Den, Den/morf e Den+morf, respectivamente 2,9, 2,8 e 2,3 mg/kg/dia. CONCLUSÕES: A morfina não promoveu a carcinogênese esofágica e pode ter estimulado o metabolismo hepático de primeira passagem do carcinógeno.

Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model.

In this study, histopathological and biochemical changes due to chronic usage of morphine or tramadol in liver and kidney were assessed in rats. Thirty male Wistar rats (180-220 g) were included and divided into three groups. Normal saline (1 ml) was given intraperitoneally as placebo in the control group (n = 10). Morphine group (n = 10) received morphine intraperitoneally at a dose of 4, 8, 10 mg/kg/day in the first, second and the third ten days of the study, respectively. Tramadol group (n = 10), received the drug intraperitoneally at doses of 20, 40 and 80 mg/kg/day in the first, second and the third ten days of the study, respectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinin, blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were measured in the serum. Liver and kidney specimens were evaluated by light microscopy. Serum ALT, AST, LDH, BUN and creatinin levels were significantly higher in morphine group compared to the control group. Serum LDH, BUN and creatinin levels were significantly increased in the morphine group compared to the tramadol group. The mean MDA level was significantly higher in morphine group compared to the tramadol and control groups (P < 0.05). Light microscopy revealed severe centrolobular congestion and focal necrosis in the liver of morphine and tramadol groups, but perivenular necrosis was present only in the morphine group. The main histopathologic finding was vacuolization in tubular cells in morphine and tramadol groups. Our findings pointed out the risk of increased lipid peroxidation, hepatic and renal damage due to long term use of opioids, especially morphine. Although opioids are reported to be effective in pain management, their toxic effects should be kept in mind during chronic usage.

Protective effect of vilva juice on glycoconjugate levels in experimentally induced constipation in rats.

Efficacy of vilva, a polyherbal formulation was evaluated in morphine induced constipated rats. Vilva juice, at a dose of 1.5 ml/100 g body wt was given orally for a period of 7 days. Morphine sulfate was injected to induce constipation on 8th day, 45 min before the experiments. Protein bound glycoconjungates were estimated in intestinal tissue. Altered levels of glycoconjugates were maintained at near normalcy when pretreated with vilva juice in morphine induced rats. Histological changes were observed in the colon tissue. The damage to crypts of Liberkunn in constipated rats were found to be reduced in vilva pretreated rats. Vilva, thus, offered significant protection against morphine induced constipation by way of augmenting mucus secretion.