RESUMEN
Electrospun nanofibers have a natural wound healing effect due to their similarity to the extracellular matrix (ECM). Nigella sativa oil, which has therapeutic properties, is used for a wide variety of applications in traditional medicine. The aim of this study was to investigate the release characteristic and wound healing performance of Nigella sativa oil (NSO) loaded polyurethane (PU) electrospun nanofibrous mats in wound dressing applications. In addition, the antibacterial activity and cytotoxicity of the electrospun mats were studied. Analyses using a scanning electron microscope (SEM) showed that PU/NSO nanofibrous mat with an average fiber diameter of 416 ± 66 nm were successfully fabricated. NSO was released at a maximum ratio of 30% from the electrospun mat, and the Korsmeyer-Peppas model was identified as best for determining the release mechanism. Significant antibacterial activity was observed against Staphylococcus aureus (90.26%) and Escherichia coli (95.75%). The developed PU/NSO nanofibrous mat increased the cell viability more than 100% in human umbilical vein endothelial cell line (HUVEC) cell line. The NSO loaded PU nanofibrous mat significantly promoted the wound healing process on a rat wound model, and its wound closure reached approximately 85% compared to the control groups on the 9th day (p < 0.01). The results indicated PU/NSO nanofibrous mat is a suitable candidate for a wound dressing.
Asunto(s)
Nanofibras , Animales , Antibacterianos/farmacología , Vendajes , Aceites de Plantas , Poliuretanos , Ratas , Staphylococcus aureusRESUMEN
Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350â¯g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5â¯mg/kg and 1â¯mg/kg), amphetamine (4â¯mg/kg), MK-801 (0.05â¯mg/kg and 0.15â¯mg/kg), scopolamine (0.4â¯mg/kg), nicotine (1â¯mg/kg) and caffeine (10â¯mg/kg and 30â¯mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10â¯mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Antagonistas Colinérgicos/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas Nicotínicos/farmacología , Inhibición Prepulso/efectos de los fármacos , Estimulación Acústica/métodos , Anfetamina/farmacología , Animales , Apomorfina/farmacología , Cafeína/farmacología , Maleato de Dizocilpina/farmacología , Masculino , Nicotina/farmacología , Inhibición Prepulso/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Escopolamina/farmacologíaRESUMEN
This study tested the hypothesis that lipopolysaccharide (LPS) lowers arterial pressure through two different mechanisms depending on the dose. Previously, we found that a low hypotensive dose of LPS (1mg/kg) lowers arterial pressure by activating vagus nerve afferents. Here we report that hypotension evoked by high dose LPS (15mg/kg) can be prevented by injecting lidocaine into the OVLT but not by vagotomy or inactivation of the NTS. The hypotension produced by both LPS doses was correlated with elevated extracellular norepinephrine concentrations in the POA and prevented by blocking alpha-adrenergic receptors. Thus, initiation of endotoxic hypotension is dose-related, mechanistically.
Asunto(s)
Presión Arterial/fisiología , Endotoxemia/fisiopatología , Hipotensión/fisiopatología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/toxicidad , Organum Vasculosum/fisiología , Animales , Presión Arterial/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Endotoxemia/inducido químicamente , Hipotensión/inducido químicamente , Masculino , Organum Vasculosum/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The symptoms of schizophrenia are evaluated in three general categories: positive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model positive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by using a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively assigned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was assigned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a significant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were significantly lower, and the average distance between rat pairs was significantly longer than HI rats. In the EPM test LI and HI rats showed similar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.
Asunto(s)
Inhibición Prepulso , Conducta Social , Estimulación Acústica , Animales , Masculino , Aprendizaje por Laberinto , Ratas Wistar , Reflejo de SobresaltoRESUMEN
It has been shown that cholinergic system plays an important role in schizophrenia-associated cognitive deficits, therefore cholinergic drugs are novel targets for the treatment of cognitive deficits seen in schizophrenia. We aimed to test the effects of CDP-choline on sensorimotor gating functioning, which is an important function for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. In this study, prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning, and the effects of CDP-choline on scopolamine induced PPI disruption were evaluated in rats. Furthermore, the contribution of the cholinergic mechanism in these effects was determined. CDP-choline (75, 250, 500mg/kg) by itself had no effect on the PPI in naïve animals. Scopolamine (0.4mg/kg; s.c.) significantly decreased the PPI levels and intraperitoneal administration of CDP-choline (250mg/kg) attenuated the effects of scopolamine. A non-specific nicotinic receptor antagonist, mecamylamine and an alpha 7 nicotinic receptor (α7-nAChR) antagonist, methyllycaconitine were used to investigate the mechanism underlying the effects of CDP-choline. Mecamylamine (3mg/kg; s.c.), and methyllycaconitine (10µg; i.c.v.) completely blocked the reversal effects of CDP-choline on scopolamine induced disruption of PPI. These results demonstrate that exogenous administration of CDP-choline attenuates scopolamine induced PPI disruption and show that the activation of central α7-nAChR may play a critical role in this effect.
Asunto(s)
Citidina Difosfato Colina/farmacología , Inhibición Prepulso/efectos de los fármacos , Escopolamina/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Aconitina/análogos & derivados , Aconitina/farmacología , Estimulación Acústica , Animales , Masculino , Mecamilamina/farmacología , Antagonistas Nicotínicos/farmacología , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidoresRESUMEN
Varenicline, a widely used smoking cessation drug, has partial agonistic activity at α4ß2 nicotinic receptors, and full agonistic activity at α7 nicotinic receptors. Thus it may interact with cognitive processes and may alleviate some of the cognitive disturbances observed in psychotic illnesses such as schizophrenia. We aimed to test the effects of varenicline on sensorimotor gating functioning, which is crucial for normal cognitive processes, especially for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. Prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning. First, the effects of varenicline and nicotine on rats having high or low baseline PPI levels were evaluated; then, varenicline was applied prior to apomorphine (0.5 mg/kg), and MK-801 (0.15 mg/kg), which are used as comparative models of PPI disruption. Varenicline (0.5-3 mg/kg) did not change PPI when given alone in naïve animals. When rats were selected according to their baseline PPI values, varenicline (1 mg/kg) significantly decreased PPI in high-inhibitory (HI) but not in low-inhibitory (LI) rats. Nicotine (1 mg/kg; tartrate salt) produced a similar activity in LI and HI groups. In combination experiments, varenicline did not reverse either apomorphine or the MK-801-induced disruption of PPI. These results demonstrate that the effects of both varenicline and nicotine on sensorimotor gating are influenced by the baseline PPI levels. Moreover, varenicline has no effect on apomorphine or the MK-801-induced disruption of PPI.
Asunto(s)
Benzazepinas/farmacología , Agonistas Nicotínicos/farmacología , Inhibición Prepulso/efectos de los fármacos , Quinoxalinas/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica/efectos adversos , Acústica , Análisis de Varianza , Animales , Apomorfina/farmacología , Maleato de Dizocilpina/farmacología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Nicotina/farmacología , Ratas , Ratas Sprague-Dawley , VareniclinaRESUMEN
Agmatine is an endogenous substance, synthesized from l-arginine, and it is proposed to be a new neurotransmitter. Preclinical studies indicated that agmatine may have an important role in the pathophysiology of schizophrenia. This study was organized to investigate plasma agmatine in patients with schizophrenia and in healthy controls. Eighteen patients with schizophrenia and 19 healthy individuals constituted the subjects. Agmatine levels in the plasma were measured using the HPLC method. The S100B protein level, which is a peripheral biomarker for brain damage, was also measured using the ELISA method. While plasma levels of agmatine in patients with schizophrenia were significantly increased (p < 0.0001) compared to those of healthy individuals (control), there were no significant changes in the levels of S100B protein (p = 0.660). An ROC (receiver operating characteristic) curve analysis revealed that measuring plasma agmatine levels as a clinical diagnostic test would significantly differentiate between patients with schizophrenia and those in the control group (predictive value: 0.969; p < 0.0001). The predictive value of S100B measurements was not statistically significant (p > 0.05). A multiple regression analysis revealed that the age of the patient and the severity of the illness, as indicated by the PANSS score, significantly contributed the plasma agmatine levels in patients with schizophrenia. These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia.
Asunto(s)
Agmatina/sangre , Esquizofrenia/sangre , Adulto , Factores de Edad , Anciano , Cromatografía Líquida de Alta Presión , Técnicas Electroquímicas , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estadísticas no Paramétricas , Turquía , Adulto JovenRESUMEN
The rats having high locomotor reactivity to a novel environment (LRNE) are known to be more vulnerable to develop locomotor sensitization, which reflects the initial neuroplastic changes in brain systems related to addictive behaviours. The present study aimed to investigate whether sensorimotor gating level, measured by prepulse inhibition (PPI) of acoustic startle reflex, also reflects vulnerability for nicotine sensitization. A batch of rats was assigned into three groups according to their baseline PPI values. The highest 1/3 and the lowest 1/3 proportions were selected and defined as high-inhibitory (HI) and low-inhibitory (LI) groups. LRNE was measured in the rats, then they were treated with nicotine (1 mg/kg, tartrate salt, subcutaneously) or saline and locomotor activity (LMA) was immediately recorded for 15 min. This procedure was performed daily for 5 successive days. After a 3-day drug-free period, all rats were challenged with nicotine (1 mg/kg) on 9th day and with saline on 12th day. Same sensitization protocol was applied in another batch of rats, except assigning them into the high-responder (HR) and low-responder (LR) groups according to LRNE levels. There was no significant difference between HI and LI rats in LRNE. Although the acute effect of nicotine on LMA was higher in HI rats, a locomotor sensitization developed and expressed only in LI rats. In the following experiments, nicotine stimulated LMA both in HR and LR rats, but induced and expressed locomotor sensitization only in HR rats. The present study shows that acute locomotor stimulant effect and locomotor sensitization developing effects of nicotine are associated with the baseline PPI and LRNE levels. But these two factors are independent from each other.
Asunto(s)
Inhibición Psicológica , Actividad Motora/efectos de los fármacos , Nicotina/administración & dosificación , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Estimulación Acústica , Análisis de Varianza , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Actividad Motora/fisiología , Ratas , Reflejo de Sobresalto/fisiología , Filtrado Sensorial/fisiologíaRESUMEN
Baseline prepulse inhibition (PPI) of the acoustic startle reflex is thought to reflect the functioning of the sensorimotor gating system in the brain. The current literature indicates that similar neurotransmitter systems may play roles both in the regulation of PPI and in the development of ethanol withdrawal syndrome (EWS). The aim of the present study was to test if individual baseline PPI levels have any relationship to the behavioral and neurochemical consequences of EWS in rats. A batch of rats (n=30) was sorted according to baseline PPI levels and classified as either high-inhibitory (HI) or low-inhibitory (LI) rats (n=10 in each group). Ethanol was administered in a liquid diet for 21 days. On the 22nd day, ethanol was removed from the diet, and EWS was induced. At the 2nd, 4th, and 6th hours of EWS, locomotor activity and behavioral symptoms were evaluated. Brain tissue concentrations of dopamine, serotonin and noradrenaline in hippocampus, cortex, and striatum were measured after the 6th hour of EWS testing. Another batch of rats (n=30) was classified using the same procedure and fed with regular diet. On the 22nd day, rats were decapitated and neurochemical measurements were repeated. HI and LI rats consumed similar amounts of ethanol. However, EWS signs such as stereotyped behaviors, wet-dog shakes, and tremor were more intense in LI rats compared to their HI counterparts. Audiogenic seizures occurred in both groups in a similar manner. Although the catecholamine concentrations in the brains of both groups were parallel under baseline conditions, dopamine levels increased in the cortex of LI and in the striatum of HI rats, whereas striatum serotonin levels decreased only in LI rats after the 6th hour of EWS. In conclusion, the data suggest that the behavioral symptoms and neurochemical changes observed in EWS may be associated with baseline PPI levels.
Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Etanol/toxicidad , Inhibición Psicológica , Reflejo de Sobresalto/fisiología , Índice de Severidad de la Enfermedad , Síndrome de Abstinencia a Sustancias/psicología , Estimulación Acústica/efectos adversos , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Etanol/administración & dosificación , Masculino , Ratas , Ratas Wistar , Conducta Estereotipada/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatologíaRESUMEN
It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.
Asunto(s)
Clozapina/farmacología , Actividad Motora/efectos de los fármacos , Nicotina/antagonistas & inhibidores , Nicotina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , Actividad Motora/fisiología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Ratas , Ratas WistarRESUMEN
Conditioned stimulus properties of venlafaxine are still unknown. In the present study, the discriminative stimulus properties of venlafaxine by using a conditioned taste aversion procedure were investigated. Swiss Webster mice were allowed to reach water from 2 pipettes for 20 min (09:00-11:30 h), plus 30 min (15:30-16:00 h), daily. During the 4 days, the test drugs [fluoxetine, escitalopram, tianeptine, reboxetine, and Nomega-nitro-L-arginine methyl ester (L-NAME)] were injected to mice at least 1 h after they had first water session. On day 5, they consumed glucose solution (5% w/v) and immediately injected with conditioning drug (venlafaxine 32 mg/kg). On day 8, mice were allowed to make a choice between water and glucose solution. The amount of glucose consumption as a percentage of total fluid intakes was calculated for each animal. Significant reduction in glucose choice was defined as conditioned taste aversion. Venlafaxine (32 mg/kg) induced a robust conditioned taste aversion in mice. Pre-exposure to tianeptine (2.5-10 mg/kg), fluoxetine (10 mg/kg), escitalopram (32 mg/kg), and reboxetine (5 mg/kg) substituted for venlafaxine by preventing the conditioned taste aversion induced by venlafaxine. L-NAME did not substitute for venlafaxine. Substitution of venlafaxine by fluoxetine, tianeptine, escitalopram, and reboxetine provides further evidence that both 5-HT and noradrenaline reuptake inhibition may play an important role in the stimulus effect of venlafaxine.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Reacción de Prevención/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Ciclohexanoles/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Gusto , Animales , Masculino , Ratones , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Clorhidrato de VenlafaxinaRESUMEN
We recently reported that the preoptic anterior hypothalamic area (POA) mediates the hypotensive response evoked by lipopolysaccharide (LPS). In this study, we investigated how the inflammatory signal induced by LPS reaches the POA. Subdiaphragmatic vagotomy and abdominal perivagal lidocaine administration, or lidocaine injection into the nucleus tractus solitarius (NTS) prevented LPS hypotension. Microinjection of the alpha-adrenergic receptor antagonist phentolamine into the POA, blocked initiation of the hypotensive response and prevented the late decompensatory phase. These data suggest that LPS hypotension is mediated by the vagus nerve which conveys the signal to the NTS and, in turn, stimulates norepinephrine release within the POA.
Asunto(s)
Hipotensión/inmunología , Hipotensión/fisiopatología , Área Preóptica/fisiopatología , Receptores Adrenérgicos alfa/metabolismo , Núcleo Solitario/fisiopatología , Nervio Vago/fisiopatología , Enfermedad Aguda , Antagonistas Adrenérgicos alfa/farmacología , Anestésicos Locales/farmacología , Animales , Hipotensión/inducido químicamente , Lidocaína/farmacología , Lipopolisacáridos/farmacología , Masculino , Fentolamina/farmacología , Área Preóptica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Choque Séptico/fisiopatología , Transducción de Señal/inmunología , Vagotomía , Nervio Vago/efectos de los fármacosRESUMEN
Severe blood loss lowers arterial pressure through a central mechanism that is thought to include opioid neurons. In this study, we investigated whether hemorrhage activates proopiomelanocortin (POMC) neurons by measuring Fos immunoreactivity and POMC mRNA levels in the medial basal hypothalamus. Hemorrhage (2.2 ml/100 g body weight over 20 min) increased the number of Fos immunoreactive neurons throughout the rostral-caudal extent of the arcuate nucleus, the retrochiasmatic area and the peri-arcuate region lateral to the arcuate nucleus where POMC neurons are located. Double label immunohistochemistry revealed that hemorrhage increased Fos expression by beta-endorphin immunoreactive neurons significantly. The proportion of beta-endorphin immunoreactive neurons that expressed Fos immunoreactivity increased approximately four-fold, from 11.7+/-1.4% in sham-operated control animals to 42.0+/-5.2% in hemorrhaged animals. Hemorrhage also increased POMC mRNA levels in the medial basal hypothalamus significantly, consistent with the hypothesis that blood loss activates POMC neurons. To test whether activation of arcuate neurons contributes to the fall in arterial pressure evoked by hemorrhage, we inhibited neuronal activity in the caudal arcuate nucleus by microinjecting the local anesthetic lidocaine (2%; 0.1 or 0.3 microl) bilaterally 2 min before hemorrhage was initiated. Lidocaine injection inhibited hemorrhagic hypotension and bradycardia significantly although it did not influence arterial pressure or heart rate in non-hemorrhaged rats. These results demonstrate that hemorrhage activates POMC neurons and provide evidence that activation of neurons in the arcuate nucleus plays an important role in the hemodynamic response to hemorrhage.
Asunto(s)
Hemorragia/fisiopatología , Hipotálamo/fisiopatología , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Bradicardia/etiología , Bradicardia/prevención & control , Hemorragia/complicaciones , Hemorragia/metabolismo , Hipotensión/etiología , Hipotensión/prevención & control , Hipotálamo/metabolismo , Hipotálamo Medio/metabolismo , Inmunohistoquímica , Inyecciones , Lidocaína/administración & dosificación , Lidocaína/farmacología , Masculino , Proopiomelanocortina/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , betaendorfina/metabolismoRESUMEN
Glycyl-glutamine (Gly-Gln) is an inhibitory dipeptide synthesized from beta-endorphin(1-31). Previously, we showed that Gly-Gln inhibits morphine conditioned place preference, tolerance, dependence and withdrawal. In this study, we tested whether Gly-Gln's inhibitory activity extends to other rewarding drugs, specifically nicotine. Rats were conditioned with nicotine (0.6 mg/kg, s.c.) for four days and tested on day five. Glycyl-glutamine (100 nmol i.c.v.) inhibited acquisition and expression of a nicotine place preference significantly. Cyclo(Gly-Gln) (100 nmol i.c.v. or 25 mg/kg i.p.), a cyclic Gly-Gln derivative, blocked expression of nicotine place preference but Gly-d-Gln (100 nmol i.c.v.) was ineffective. To study nicotine withdrawal, rats were treated with nicotine (9 mg/kg/day) for seven days and conditioned place aversion was induced with mecamylamine (1 mg/kg, s.c.). Glycyl-glutamine blocked acquisition of place aversion to mecamylamine but not U50,488, a kappa opioid receptor agonist. Glycyl-glutamine thus inhibits the rewarding effects of nicotine and attenuates withdrawal in nicotine dependent rats.
Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Dipéptidos/farmacología , Nicotina/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Mecamilamina/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Péptidos Cíclicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Síndrome de Abstinencia a Sustancias/prevención & control , Factores de TiempoRESUMEN
Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized from beta-endorphin(1-31). Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and beta-endorphin(1-31), but it does not interfere with opioid analgesia. In this study, we tested whether Gly-Gln administration would influence morphine-induced conditioned place preference, tolerance, dependence, or withdrawal. For place preference experiments, rats were conditioned with morphine sulfate (2.5 mg/kg i.p.) or saline on alternate days for 6 days and tested on day 7. Glycyl-glutamine (1-100 nmol i.c.v.) pretreatment inhibited acquisition of a conditioned place preference to morphine significantly. Glycyl-glutamine (100 nmol i.c.v.) also blocked expression of a pre-established morphine place preference, but it did not interfere with acquisition of a conditioned place preference to palatable food, and it did not produce place preference or aversion when given alone to morphine-naive animals. To induce antinociceptive tolerance, rats were treated with morphine (10 mg/kg i.p.) twice daily for 7 days, and morphine antinociception was evaluated with the tail-flick test. Glycyl-glutamine (100 nmol i.c.v.) pretreatment delayed the onset of morphine tolerance significantly and partially reversed pre-established tolerance. Morphine dependence and withdrawal were assessed by measuring naloxone-precipitated withdrawal symptoms. Glycyl-glutamine inhibited the development of morphine dependence when given to rats twice daily immediately before they received morphine (10 mg/kg i.p.) and suppressed withdrawal symptoms of rats with subcutaneously implanted morphine pellets when administered 5 min before withdrawal was induced with naloxone. Glycyl-glutamine thus attenuates morphine-induced conditioned place preference, tolerance, dependence, and withdrawal without compromising morphine analgesia.
Asunto(s)
Analgésicos Opioides/antagonistas & inhibidores , Condicionamiento Operante/efectos de los fármacos , Dipéptidos/farmacología , Dependencia de Morfina/prevención & control , Morfina/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/prevención & control , betaendorfina/farmacología , Analgésicos Opioides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Dipéptidos/administración & dosificación , Dipéptidos/química , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Alimentos , Inyecciones Intraventriculares , Masculino , Morfina/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , betaendorfina/químicaRESUMEN
This study investigated whether the lateral hypothalamus (LH) contributes to the depressor response evoked by somato-visceral nociception. Lidocaine (2%; 0.1, 0.3 or 1.0 microl) or muscimol (0.34 nmol; 0.5 microl) was microinjected into the rostral LH of halothane-anesthetized rats bilaterally and somato-visceral nociception was induced 2 min later by injecting 5% acetic acid (0.5 ml) intraperitoneally. Lidocaine and muscimol inhibited the hypotension and bradycardia caused by somato-visceral nociception significantly without affecting cardiovascular function in normotensive animals.
Asunto(s)
Bradicardia/fisiopatología , Agonistas del GABA/administración & dosificación , Homocisteína/análogos & derivados , Hipotensión/fisiopatología , Área Hipotalámica Lateral/efectos de los fármacos , Muscimol/administración & dosificación , Animales , Bradicardia/etiología , Fenómenos Fisiológicos Cardiovasculares , Homocisteína/administración & dosificación , Hipotensión/etiología , Masculino , Microinyecciones , Dolor/complicaciones , Dolor/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
This study tested the hypothesis that the ventrolateral column of the midbrain periaqueductal gray (vlPAG) region mediates the hypotension and bradycardia evoked by visceral nociception. To test this, the local anesthetic lidocaine (2%; 0.5 microl) was microinjected into the vlPAG of halothane-anesthetized rats bilaterally and visceral nociception was induced 2 min later by injecting 5% acetic acid (0.5 ml) intraperitoneally. Acetic acid injection caused an abrupt fall in arterial pressure (-12.2+/-2.1 mm Hg) and heart rate (-37+/-93 bpm) lasting approximately 15 min. Lidocaine injection into the vlPAG prevented the fall in arterial pressure and heart rate completely. Cobalt chloride (5 mM; 0.2 or 0.5 microl) injection into the vlPAG also prevented nociceptive hypotension but it did not affect the fall in heart rate significantly. Lidocaine pretreatment also inhibited the depressor response caused by intramuscular formalin (5%; 0.2 ml) administration, a model of deep somatic nociception, although it did not prevent the response completely. To determine if opioid receptors mediate the response, selective mu, delta or kappa opioid receptor antagonists were microinjected into the vlPAG 5 min before intraperitoneal (ip) acetic acid administration. Naltrindole, a delta receptor antagonist, inhibited the response significantly but mu and kappa antagonists were completely ineffective. Lidocaine and naltrindole had no effect when injected into the dorsolateral PAG and did not influence cardiovascular function when injected into the vlPAG of saline treated control animals. These data support the hypothesis that the vlPAG mediates the depressor response evoked by visceral nociception and indicate that delta opioid receptors participate in the response.
Asunto(s)
Hipotensión/fisiopatología , Dimensión del Dolor/métodos , Sustancia Gris Periacueductal/fisiología , Receptores Opioides delta/fisiología , Animales , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Opioides delta/antagonistas & inhibidoresRESUMEN
Intravenous (i.v.) administration of cytidine-5'-diphosphate choline (CDP-choline) (100, 250 and 500 mg/kg) increased blood pressure in normal rats and reversed hypotension in haemorrhagic shock. Choline (54 mg/kg; i.v.), at the dose equimolar to 250 mg/kg CDP-choline decreased blood pressure of rats in both conditions and caused the death of all hypotensive animals within 2-5 min. Equimolar dose of cytidine (124 mg/kg; i.v.) did not change cardiovascular parameters. Choline levels in plasma, lateral cerebral ventricle and hypothalamus increased after CDP-choline administration. Intracerebroventricular (i.c.v.) hemicholinium-3 pretreatment (20 microg), greatly attenuated the pressor effect of CDP-choline in both conditions. Atropine pretreatment (10 microg; i.c.v.) did not change the pressor effect of CDP-choline while mecamylamine (50 microg; i.c.v.) abolished the pressor response to drug. Besides, acetylcholine (1 micromol; i.c.v.) produced similar increases in blood pressure in normal and hypotensive conditions to that observed in CDP-choline given rats. CDP-choline (250 mg/kg; i.v.) increased plasma catecholamines and vasopressin levels but not plasma renin activity. Pretreatment of rats with either prazosin (0.5 mg/kg; i.v.) or vasopressin V(1) receptor antagonist, [beta-mercapto,beta,beta-cyclopentamethylenepropionyl(1),O-Me-Tyr(2)-Arg(8)]vasopressin (10 microg/kg; i.v.), attenuated the pressor response to CDP-choline while simultaneous administration of these antagonists before CDP-choline injection completely blocked the pressor effect. Results show that i.v. CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. Activation of central nicotinic cholinergic mechanisms by the increases in plasma and brain choline concentrations appears to be involved in the pressor effect of this drug. Moreover, the increases in plasma catecholamines and vasopressin levels mediate these effects.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Citidina Difosfato Colina/farmacología , Hipotensión/tratamiento farmacológico , Choque Hemorrágico/tratamiento farmacológico , Animales , Encéfalo/metabolismo , Catecolaminas/sangre , Colina/metabolismo , Citidina Difosfato Colina/administración & dosificación , Relación Dosis-Respuesta a Droga , Hipotensión/etiología , Inyecciones Intravenosas , Masculino , Nootrópicos/administración & dosificación , Nootrópicos/farmacología , Ratas , Ratas Wistar , Receptores Nicotínicos/metabolismo , Choque Hemorrágico/fisiopatología , Vasopresinas/sangreRESUMEN
Intracerebroventricular (i.c.v.) administration of CDP-choline (0.25, 0.5, 1 and 2 micromol) induced prompt, dose- and time-dependent increase in blood pressure in normotensive rats. Equimolar dose of CDP-choline (1 micromol; i.c.v.) and choline (1 micromol; i.c.v.) caused similar increases in blood pressure while cytidine (1 micromol; i.c.v.) failed to produce any pressor effect. In haemorrhagic shock, CDP-choline (0.1, 0.25, 0.5 and 1 micromol; i.c.v.) increased blood pressure dose- and time-dependently. The complete reversal of hypotension was observed with the i.c.v. injection of CDP-choline (1 micromol) and choline (1 micromol). Cytidine (1 micromol; i.c.v.) produced small, but significant ( P<0.05) increase in blood pressure in haemorrhaged rats. Dose-related bradycardia was observed with the injection of CDP-choline in normotensive rats, but the changes in heart rate were not significantly different ( P>0.05) in hypotensive conditions. Choline levels in lateral cerebral ventricle and hypothalamus increased about nine- and fivefold, respectively, after CDP-choline (1 micromol) administration in normotensive rats. In haemorrhagic shock extracellular choline levels in hypothalamus increased sevenfold after an i.c.v. administration of CDP-choline (1 micromol). Hemicholinium-3 (20 microg; i.c.v.), a neuronal high affinity choline uptake blocker, and mecamylamine (50 microg; i.c.v.), nicotinic receptor antagonist, pretreatment abolished the pressor effect of CDP-choline in normal rats. The increase in blood pressure was also attenuated by atropine (10 microg; i.c.v.) pretreatment. Atropine blocked the bradycardic response observed after CDP-choline. In haemorrhaged rats, the pressor effect of CDP-choline was attenuated by hemicholinium-3 and mecamylamine while atropine failed to alter the pressor response to CDP-choline. I.c.v. CDP-choline increased plasma adrenaline and vasopressin levels in normal rats. Haemorrhage, itself, increased plasma catecholamines and vasopressin levels. CDP-choline (1 micromol) produced additional increases in the elevated plasma levels of these hormones. An alpha(1)-adrenoceptor blocker, prazosin (0.5 mg/kg; i.v.), or vasopressin V(1) receptor antagonist, [beta-mercapto, beta,beta-cyclopenta-methylenepropionyl(1), O-Me-Tyr(2)-Arg(8)]-vasopressin (10 micro/kg; i.v.), pretreatments partially blocked the pressor response to CDP-choline (1 micromol; i.c.v.). Simultaneous administration of these two antagonists completely blocked the pressor effect of CDP-choline in haemorrhagic shock. These results show that the exogenous administration of CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. In normotensive conditions, increase in blood pressure appears to be due to the activation of both nicotinic and muscarinic central cholinergic receptors through the activation of presynaptic cholinergic mechanisms. In hypotensive rats, activation of nicotinic cholinergic receptors is solely involved in the pressor effect. Increase in plasma vasopressin and adrenaline mediates the pressor response of CDP-choline in both normotensive and hypotensive conditions.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Colina/metabolismo , Hipotensión/fisiopatología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Catecolaminas/sangre , Ventrículos Cerebrales/metabolismo , Colina/farmacología , Antagonistas Colinérgicos/farmacología , Citidina Difosfato Colina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hipotensión/tratamiento farmacológico , Hipotensión/metabolismo , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Choque Hemorrágico/tratamiento farmacológico , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatología , Factores de Tiempo , Vasopresinas/sangreRESUMEN
Intracerebroventricular (i.c.v.) injection of choline (50-150 microg), a precursor of the neurotransmitter acetylcholine, produced a time-and dose-dependent increase in plasma vasopressin levels in conscious, freely moving rats. The increase in plasma vasopressin in response to i.c.v. choline (150 microg) was inhibited by pretreatment with the nicotinic receptor antagonist, mecamylamine (50 microg; i.c.v.), but not by the muscarinic receptor antagonist, atropine (10 microg; i.c.v). The choline-induced rise in plasma vasopressin levels was greatly attenuated by hemicholinium-3 (HC-3; 20 microg; i.c.v.), a neuronal choline uptake inhibitor. Choline (50 or 150 microg; i.c.v.) produced a much greater increase in plasma vasopressin levels in osmotically stimulated or hemorrhaged rats than in normal rats. Choline (150 microg; i.c.v.) also enhanced plasma vasopressin response to graded hemorrhage; the enhancing effect of choline was also attenuated by HC-3 (20 microg; i.c.v.). Choline and acetylcholine concentrations in hypothalamic dialysates increased significantly following i.c.v. injection of choline (150 microg). It is concluded that choline increases plasma vasopressin levels by stimulating central nicotinic receptors indirectly, through the enhancement of acetylcholine synthesis and release, and augments the ability of osmotic stimulations or hemorrhage to stimulate vasopressin release.