Amplitud de distribución eritrocitaria un biomarcador inflamatorio relacionado a retinopatía diabética proliferativa / Red Blood Cell Distribution Width An Inflammatory Biomarker Related To Proliferative Diabetic Retinopathy

Objetivo: El objetivo de este estudio fue determinar la asociación entre el ancho de distribución de glóbulos rojos y la retinopatía diabética proliferativa en pacientes con diabetes tipo 2. Métodos: Realizamos un estudio de casos y controles en un hospital. Pacientes adultos (≥ 18 años) con diagnóstico de Retinopatía Diabética que fueron sometidos a controles médicos en el servicio de Oftalmología donde se inscribieron en nuestro estudio. Seleccionamos un tamaño de muestra total de 262 pacientes, de los cuales 131 casos tenían retinopatía diabética proliferativa y 131 controles tenían retinopatía diabética no proliferativa. Se registraron datos sobre edad, sexo, índice de masa corporal, antecedentes de hipertensión, nefropatía diabética, insuficiencia cardíaca congestiva, hemoglobina y HbA1c para las personas que cumplieron con los criterios de inclusión. Se utilizó un modelo de razón de probabilidades para probar la relación entre el ancho de distribución de glóbulos rojos y la retinopatía diabética proliferativa. Resultados: El ancho medio de distribución de glóbulos rojos +/- DE de los casos fue 14,41 +/- 0,84 y los controles fue 13,49 +/- 1,26. De acuerdo con el análisis bivariado, se encontró una asociación entre el ancho de distribución de los glóbulos rojos y la retinopatía diabética proliferativa (OR 3,79, P = 0,000, IC = 2,12-6,78). El análisis de regresión logística multivariante indicó que el ancho de distribución de glóbulos rojos (OR 2,15, P = 0,037, IC = 1,05-4,43) era un factor de riesgo independiente para el desarrollo de retinopatía diabética proliferativa. Conclusión: Los valores elevados del ancho de distribución de glóbulos rojos se relacionaron con la retinopatía diabética proliferativa, lo que sugiere la posible aplicación del ancho de distribución de glóbulos rojos como un biomarcador predictivo accesible de la progresión de la enfermedad en pacientes con retinopatía diabética.

Objective: The aim of this study was to determine the association between Red Blood cell Distribution width and Proliferative Diabetic Retinopathy in patients with type 2 diabetes. Methods: We conducted a hospital-based case-control study. Adult patients (≥ 18 years old) with the diagnosis of Diabetic Retinopathy who underwent medical check-ups at the ophthalmology department where enrolled in our study. We selected a total sample size of 262 patients, of which 131 cases had Proliferative Diabetic Retinopathy and 131 controls had Non Proliferative Diabetic Retinopathy. Data about age, gender, body mass index, history of hypertension, diabetic nephropathy, Congestive heart failure, Hemoglobin and HbA1c were registered for individuals who met inclusion criteria. Odds ratio model was used to test the relationship between Red Blood Cell Distribution Width and Proliferative Diabetic Retinopathy. Results: Mean Red Blood cell Distribution width +/- SD of the cases was 14.41+/-0.84 and the controls was 13.49+/-1.26. According to bivariate analysis, an association was found between Red Blood cell Distribution width and Proliferative Diabetic Retinopathy (OR 3.79, P=0.000, IC=2.12-6.78). Multivariate logistic regression analysis indicated that Red Blood cell Distribution width (OR 2.15, P=0.037, IC= 1.05-4.43) was an independent risk factors for the development of Proliferative Diabetic Retinopathy. Conclusion: Elevated values of Red Blood cell Distribution width were related to Proliferative Diabetic Retinopathy, suggesting the potential application of Red Blood cell Distribution width as an accessible predictive biomarker of disease progression in patients with diabetic retinopathy.

Enfermedad por reflujo gastroesofágico como factor asociado a asma bronquial en población pediátrica / Gastroesophageal Reflux Disease As A Factor Associated With Bronchial Asthma In The Pediatric Population

Objetivo: Determinar la relación entre enfermedad por reflujo gastroesofágico y asma bronquial en población pediátrica en el hospital Nacional del Niño entre los años 2017-2018. Métodos: Se realizó un estudio observacional analítico tipo casos y controles no emparejado de razón 1 caso para 2 controles, con un total de 45 casos y 90 controles, se realizó un muestreo probabilístico aleatorio simple, con una recolección retrospectiva para las variables asma bronquial, ERGE, esofagitis inducida por ERGE, prematuridad, lactancia materna interrumpida, sexo y edad. Se realizó un modelo de regresión logística bivariado y múltiple para la obtención del Odds Ratio para la fuerza de asociación. Resultados: Se encontró una diferencia estadísticamente significativa para ERGE (p=0,002), siendo 33,33% y 11,11% para los casos y controles, así como para lactancia interrumpida (p=0,013); por análisis de regresión logística múltiple las variables ERGE (OR 4,27, p=0,003, IC 1,64-10,92) y lactancia materna interrumpida (OR 2,74, P=0,011, IC 1,26-5,97) presentaron relación para asma bronquial. Conclusión: Se encontró una relación entre ERGE y asma bronquial la cual puede ser extrapolada a la población pediátrica de la ciudad de Lima, este es el primer artículo publicado al respecto a nivel nacional, se recomiendan estudios prospectivos para determinar causalidad.

Objective: To determine the relationship between gastroesophageal reflux disease and bronchial asthma in the pediatric population of the National Children's Hospital Breña headquarters between the years 2017-2018. Methods: An analytical observational study of cases and controls was not matched, with a ratio of 1 case to 2 controls, with a total of 45 cases and 90 controls, a simple random probability sampling was performed, with a retrospective collection for the variables bronchial asthma, GERD, GERD-induced esophagitis, prematurity, interrupted breastfeeding, sex and age. A bivariate and multiple logistic regression model was performed to obtain the Odds Ratio for the strength of association. Results: A statistically significant difference was found for GERD (p = 0.002), being 33.33% and 11.11% for cases and controls, as well as for interrupted lactation (p = 0.013); by multiple logistic regression analysis the variables GERD (OR 4.27, p = 0.003, CI 1.64-10.92) and interrupted breastfeeding (OR 2.74, P = 0.011, CI 1.26-5.97 ) presented a relationship for bronchial asthma. Conclusion: A relationship was found between GERD and bronchial asthma which can be extrapolated to the pediatric population of the city of Lima, this is the first article published in this regard at the national level, prospective studies are recommended to determine causality.

Índice cintura talla un marcador de obesidad visceral relacionado a cistitis no complicada / Index Waist Size A Visceral Obesity Marker Related To Non-Complicated Cystitis

Objetivo: Determinar la relación entre el índice cintura-talla y la presencia de cistitis no complicada en los pacientes de consulta externa en un centro de atención primaria de Lima en el año 2018. Métodos: Se realizó un diseño observacional analítico, tipo casos y controles. Con una muestra de 131 casos y 131 controles, por muestreo aleatorio simple, sometidos a criterios de selección. Se revisó historias clínicas para la obtención retrospectiva de los datos. Se calculó el Odds Ratio como medida de asociación. Resultados: La media del índice cintura talla para cistitis no complicada fue de 61,91 ± 6.39 para los casos y 58.12 ± 3.87 para los controles. Se encontró asociación estadísticamente significativa entre la presencia de cistitis y el índice- cintura talla (OR 5,27; IC95% 3,10 ­ 8,95; p <0,001). Asimismo, se encontró asociación con el perímetro abdominal (OR 2,11 IC 95% 1,26 ­ 3,55; p=0,005) e IMC (OR 2,02; IC95% 1,20 ­ 3,37; p=0,007). Conclusión: El índice cintura talla tuvo una fuerte asociación con la presencia de cistitis no complicada. Se sugieren estudios prospectivos para corroborar la asociación entre marcadores de obesidad visceral y el desarrollo de infección de tracto urinario.

Objective: The aim of this study was to determine the association between waist to height ratio and uncomplicated cystitis in a primary health care center in Lima, during the year 2018. Methods: We conducted an observational, analytical, case-control study, in which a total of 131 cases and 131 controls were obtained by simple random sample, applying exclusion and inclusion criteria. Retrospective recollection of the data was performed using the medical record of each selected patient. Odds ratio was calculated to measure the strength of association. Results: the waist to height ratio mean for uncomplicated cystitis was 61,9 ± 6.39 and 58.12 ± 3.87 for the controls. We found an statistical significant association between uncomplicated cystitis and waist to height ratio (OR 5,27; 95%CI 3,10 ­ 8,95; p <0,001). Waist circumference (OR 2,11 95%CI;1,26 ­ 3,55; p=0,005) and body mass index (OR 2,02; 95%CI 1,20 ­ 3,37; p=0,007) were also associated. Conclusion: we found a strong association between waist to height ratio and uncomplicated cystitis, prospective studies are suggested to confirm the association between visceral obesity and the appearance of urinary tract infections

Antiallodynic interaction and motor performance of the pregabalin/thioctic acid and pregabalin/α-tocopherol combinations in neonatal streptozotocin-induced diabetic rats.

Painful peripheral neuropathy can be associated with nerve damage caused by diabetes mellitus. Although pregabalin is the first-line therapy for peripheral neuropathy, it shows substantial discontinuation rates, mainly because of nervous system side effects as motor incoordination. Multimodal therapy may improve the motor side effect profile of pregabalin. The aim of this study was to evaluate the interaction of pregabalin + thioctic acid or pregabalin + α-tocopherol on allodynia and motor performance in neonatal streptozotocin-induced diabetic rats. Efficacy of drugs separately or in combination was tested by tactile allodynia using von Frey filaments. Isobolographic and interaction index analysis were used to determine the antiallodynic interaction between pregabalin and either thioctic acid or α-tocopherol. Motor performance was measured using a rotarod test. Pregabalin, thioctic acid, and α-tocopherol reduced, in a dose-dependent fashion, tactile allodynia. Pregabalin + thioctic acid and pregabalin + α-tocopherol combinations also dose-dependently reduced allodynic behavior in diabetic rats. Isobolographic analysis revealed an additive interaction for both combinations. Consistently, the interaction indices confirmed the additive effect between pregabalin + thioctic acid and pregabalin + α-tocopherol. In addition, the administration of either combination improved motor incoordination induced by pregabalin. Data suggests that thioctic acid or α-tocopherol could positively impact the therapeutic profile of pregabalin, because they might be useful for reducing motor incoordination associated to pregabalin in patients with peripheral neuropathy.

Acute Consumption of Resistant Starch Reduces Food Intake but Has No Effect on Appetite Ratings in Healthy Subjects.

Previous studies have shown the benefits of native banana starch (NBS) supplementation in improving glucose metabolism and reducing body weight (BW) in humans. However, the effect of this starch on appetite regulation is unknown. The aim of this study was to examine the effects of NBS rich resistant starch on subjective measurements of appetite, energy intake, and appetite hormones in healthy subjects. Postprandial glucose and insulin responses were also assessed. In a randomized, single-blind, crossover study, 28 healthy young subjects consumed a beverage containing either 40 g of NBS or 40 g of digestible corn starch (DCS) on two separate occasions. Effects on appetite were estimated using visual analogue scales (VAS) and satiety hormone responses. At the end of the intervention, participants were provided with a pre-weighed ad libitum homogeneous test meal. After a washout period of 1 week, subjects received the alternative treatment. NBS supplementation induced a reduction in food intake, glucose area under the curve (AUC)-180 min, and insulin AUC-180 min. However, there was no associated effect on the subjective appetite ratings or gut hormones. NBS supplementation may help to reduce meal size and control BW.

Satisfacción personal de mujeres en condiciones de vulnerabilidad de Ciudad Guzmán, Jalisco / Personal satisfaction of women in conditions of vulnerability of Ciudad Guzman, Jalisco

Resumen Introducción: Las mujeres en condiciones de vulnerabilidad de sectores específicos de la población deben lidiar con circunstancias que ponen en riesgo su autoestima y satisfacción personal con la vida que llevan. Objetivo: Evaluar los niveles de satisfacción de las mujeres en condiciones de vulnerabilidad de Ciudad Guzmán, Jalisco, a partir de la autopercepción que muestran de su situación de vida. Metodología: Estudio descriptivo correlacional llevado a cabo en junio de 2016. Participaron 122 mujeres beneficiarias de despensa, que respondieron al instrumento ISPRELEBA. Se comparó el puntaje global de insatisfacción con las condiciones de vulnerabilidad y las variantes sociodemográficas con una prueba de Chi-cuadrado de Pearson. Resultados: Los sectores vulnerables que mayores niveles de insatisfacción personal presentan son las mujeres solas o en viudez, las embarazadas y en periodo de lactancia, cuyo nivel de estudios no cubre la escuela básica. Conclusiones: Se encontraron escasas iniciativas para atender problemas emocionales de las involucradas. Se sugiere un programa de atención psicológica e integración social que estimule el progreso individual de las mujeres vulnerables.

Abstract Introduction: The vulnerability conditions of specific sectors of population have to deal with circumstances that jeopardize their self-concept and personal satisfaction with their lifestyle. Objective: Evaluate the satisfaction levels of women in conditions of vulnerability in Ciudad Guzman, Jalisco, according to the self-perception of their life situation. Methodology: Correlational descriptive study implemented in June 2016. 122 beneficiary women answered the ISP-RELEBA instrument. The global score of dissatisfaction was compared with the vulnerability conditions and sociodemographic variables with a Pearson's Chi-squared test. Results: The vulnerable sectors with highest personal dissatisfaction levels are lonely women and widows, followed by pregnant and breastfeeding women, whose educational levels do not cover the basic school. Conclusion: There are few initiatives to attend to the psychological problems of those involved. It is suggested a psychological assistant and social integration program which stimulate the individual progress of vulnerable women.

Antihyperalgesic Effects of Indomethacin, Ketorolac, and Metamizole in Rats: Effects of Metformin.

Preclinical Research Metformin-dependent mechanisms have been implicated in the antinociceptive effect of some non-steroidal anti-inflammatory drugs (NSAIDs). In this study, the effect of local peripheral or systemic administration of metformin on the local peripheral or systemic antinociception induced by indomethacin, ketorolac and metamizole was assessed in the rat carrageenan-induced thermal hyperalgesia model. Rats were injected with carrageenan (1%, 50 µl) into the right hindpaw which reduced paw withdrawal latency, a measure of thermal hyperalgesia. Local peripheral or systemic administration of indomethacin, ketorolac or metamizole dose-dependently reduced carrageenan-induced thermal hyperalgesia. Local peripheral pre-treatment with metformin (800 µg/paw) partially inhibited the anti-hyperalgesic effect of indomethacin (200 µg/paw) and metamizole (200 µg/paw), but not that of ketorolac (200 µg/paw). In contrast, systemic pre-treatment with metformin (200 mg/kg) attenuated the antihyperalgesic effect of metamizole (10 mg/kg), but not that observed with either indomethacin (10 mg/kg) or ketorolac (10 mg/kg). These findings suggest that some but not all NSAIDs have effects mediated by metformin-dependent mechanisms. Drug Dev Res 78 : 98-104, 2017. ©2017 Wiley Periodicals, Inc.

Fosinopril Prevents the Development of Tactile Allodynia in a Streptozotocin-Induced Diabetic Rat Model.

The aim of this study was to evaluate fosinopril-induced changes in hemodynamic parameters and tactile allodynia in a rat model of diabetes. Diabetes was induced by streptozotocin (STZ; 50 mg/kg, i.p.) in male Wistar rats. STZ produced hyperglycemia, weight loss, polydipsia, polyphagia, and polyuria as well as long-term arterial hypotension, bradycardia, and tactile allodynia at 10-12 weeks. Daily administration of the angiotensin converting enzyme inhibitor, fosinopril (25 mg/kg, p.o., for 11 weeks) partially reduced the loss of body weight, decreased hyperglycemia, and systolic blood pressure in diabetic rats. Likewise, systemic administration of fosinopril prevented the development and maintenance of tactile allodynia in STZ-induced diabetic rats. These data suggest that fosinopril may have a role in the pharmacotherapy of diabetic neuropathic pain.

Blockade of peripheral and spinal Na+/H+ exchanger increases formalin-induced long-lasting mechanical allodynia and hyperalgesia in rats.

The Na(+)/H(+) exchanger (NHE) is involved in the regulation of intracellular pH and volume by mediating the electroneutral transport of H(+) against an influx of Na(+) ions. Since NHE1 regulates pH in neurons and astrocytes and it is expressed in nociceptive nerve fibers, it is likely that NHE may modulate neuronal excitability and pain transmission. The purpose of this study was to assess the participation of peripheral and spinal NHE in the secondary allodynia/hyperalgesia induced by formalin. In addition, we determined whether formalin injection modifies the expression of NHE1 in lumbar dorsal root ganglia (DRG) and dorsal spinal cord. Subcutaneous injection of 0.5% formalin into the dorsal surface of the hind paw produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-lasting bilateral secondary mechanical allodynia/hyperalgesia. Peripheral and intrathecal pre-treatment (-10min) with selective NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30µM), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30µM) and [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine dihydrochloride (zoniporide, 0.03-3µM) significantly increased 0.5% formalin-induced bilateral long-lasting secondary allodynia/hyperalgesia. Contrariwise, local peripheral or intrathecal post-treatment (day 6 postinjection) with these NHE inhibitors did not affect formalin-induced nociceptive behaviors. Formalin injection reduced NHE1 expression in ipsilateral and contralateral spinal dorsal horns from day 1 to 12. In addition, formalin diminished NHE1 protein expression in DRG at day 12. These results suggest that NHE1 plays a role in pain processing at peripheral and spinal levels in formalin-induced long-lasting nociceptive behaviors. Additionally, these results suggest that proteins involved in pH regulation could be targets for the development of new analgesic drugs.

Sildenafil and glyceryl trinitrate reduce tactile allodynia in streptozotocin-injected rats.

The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients.

Role of opioid receptors in the reduction of formalin-induced secondary allodynia and hyperalgesia in rats.

This study assesses the effects of peripheral or intrathecal pre-treatment or post-treatment with micro, delta, kappa and nociceptin/orphanin FQ (NOP) opioid receptor agonists (morphine, U-50488 [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride], DADLE [D-Ala2-Leu5-enkephalin] and nociceptin, respectively) on formalin-induced secondary mechanical allodynia and hyperalgesia in rats. 1% Formalin injection produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term tactile secondary allodynia and hyperalgesia. Neither peripheral (into the formalin-injected paw) nor intrathecal morphine post-treatment reversed formalin-induced secondary allodynia and hyperalgesia. In contrast, morphine pre-treatment prevented the development of these pain behaviors. Intrathecal and peripheral post- but not pre-treatment with U-50488 or DADLE significantly reduced secondary allodynia and hyperalgesia. Interestingly, nociceptin reduced both pain behaviors regardless of the administration site or treatment time. Local antinociceptive effects of morphine, DADLE, U-50488 or nociceptin were blocked by naltrexone, naltrindole, 5-guanidinonaltrindole and [Nphe(1)]nociceptin(1-13)NH(2), respectively. These results suggest that the long-term nociceptive behaviors induced by formalin are differentially modulated by selective opioid receptor agonists. In addition, data suggest that peripheral and spinal delta and kappa opioid receptors are important when nociceptive behaviors are established. In contrast, micro opioid receptors are more important at the beginning of the injury when the sensory system has not changed. NOP receptors participate diminishing both the development and maintenance of nociceptive behaviors. Results suggest that a barrage of afferent input induced by formalin injection initiates a long-term differential change in peripheral and spinal processing that affect the efficacy of opioid receptor agonists.

Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats.

Anticonvulsants, including gabapentin and carbamazepine, have shown activity against several types of neuropathic pain; however, they have limiting side effects that may minimize their use. In this study the possible synergistic interaction between anticonvulsants and benfotiamine or cyanocobalamin on spinal nerve ligation-induced tactile allodynia was assessed. Oral administration of gabapentin (15-300 mg/kg), carbamazepine (10-300 mg/kg), benfotiamine (30-600 mg/kg) or cyanocobalamin (0.3-6.0 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with gabapentin 300 mg/kg (approximately 70%), carbamazepine 300 mg/kg (approximately 66%), benfotiamine 600 mg/kg (approximately 51%) and cyanocobalamin 6 mg/kg (approximately 59%). At the highest tested doses, gabapentin, but not carbamazepine, benfotiamine or cyanocobalamin, significantly reduced motor coordination. Coadministration of gabapentin or carbamazepine with benfotiamine or cyanocobalamin in a fixed ratio markedly reduced spinal nerve ligation-induced tactile allodynia, showing a synergistic interaction between anticonvulsants and B vitamins. Data indicate that combinations of anticonvulsants with benfotiamine or cyanocobalamin are able to reduce tactile allodynia without affecting motor coordination in rats, and suggest the possible clinical use of these combinations in the treatment of neuropathic pain in humans.

Possible participation of the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway in the peripheral antinociception of melatonin.

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG)-K(+) channel pathway on melatonin-induced local antinociception was assessed during the second phase of the formalin test. The local peripheral ipsilateral, but not contralateral, administration of melatonin (150-600 microg/paw) produced a dose-related antinociception during both phases of the formalin test in rats. Moreover, local pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor, 10-100 microg/paw), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 5-50 microg/paw), (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo [1,2,3-fg:3',2',1'-kl]pyrrolo [3,4-i][1,6] benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor, 50-500 ng/paw), glibenclamide (ATP-sensitive K(+) channel blocker, 5-50 microg/paw), apamin (small-conductance Ca(2+)-activated K(+) channel blocker, 0.1-1 microg/paw) or charybdotoxin (large- and intermediate-conductance Ca(2+)-activated K(+) channel blocker, 0.03-0.3 microg/paw), but not N(G)-D-nitro-arginine methyl ester (D-NAME, inactive isomer of L-NAME, 100 microg/paw) or vehicle, significantly prevented melatonin (300 microg/paw)-induced antinociception. Data suggest that melatonin-induced local peripheral antinociception during the second phase of the test could be due to activation of the NO-cyclic GMP-PKG-ATP-sensitive and Ca(2+)-activated K(+) channels pathway.

Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats.

The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.

Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.

The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.

Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats.

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.