Complete essential oils of Laurus nobilisinducing antinociceptiveaction by opioid mechanism in C-Reflex and spinal Wind-Up model in rat / Aceites esenciales totales de Laurus nobilis inducen acción antinociceptivamediante mecanismo opioide en el modelode Reflejo-C y Wind-Up espinal en ratas

The essential oil of Laurus nobilis L. was used to test their antinociceptive efficacy. It was applied intraperitoneally (i.p.) to rats subjected to a nociception test (C reflex and spinal wind-up). The results showed that the essential oil applied at higher doses (0.06 mg/Kg) causes a complete abolition of the spinal wind-up, while the C reflex was unchanged, indicating a clear antinociceptive effect. At lower concentrations (0.012 mg/Kg), there was a lowering in the wind-up by 85% within ten minutes of the essential i.p. oil application. Interestingly, there was an effect of naloxone (0.08 mg/Kg i.p.) When applied, a change occurs that almost entirely reversed the antinociception caused by the essential oil from Laurus nobilis. We conclude that there is a significant antinociceptive effect of the essential oil of Laurus nobilis subjected to electric nociception. In addition, it was observed that naloxone reversed the antinociceptive effect (wind-up) produced by Laurus nobilis.

El aceite esencial de Laurus nobilis L. se usó para probar su eficacia antinociceptiva. Se aplicó por vía intraperitoneal (i.p.) a ratas sometidas a una prueba de nocicepción (reflejo-C y wind-up espinal). Los resultados mostraron que el aceite esencial aplicado a dosis más altas (0.06 mg/Kg) abolió completamente el wind-up espinal, mientras que el reflejo-C no cambió, lo que indica un claro efecto antinociceptivo. A concentraciones más bajas (0.012 mg/Kg), hubo una disminución en el wind-up en un 85% dentro de los diez minutos del i.p. la aplicación del aceite esencial. Curiosamente, hubo un efecto de la naloxona (0.08 mg/Kg i.p.) la cual revierte casi por completo la antinocicepción causada por el aceite esencial de Laurus nobilis. Concluimos que existe un efecto antinociceptivo significativo del aceite esencial de Laurus nobilis sometido a nocicepción eléctrica. Además, se observó que la naloxona revirtió el efecto antinociceptivo (wind-up) producido por Laurus nobilis.

A Review of the Actions of Endogenous and Exogenous Vasoactive Substances during the Estrous Cycle and Pregnancy in Rats.

Vascular endothelium plays a key role in regulating cardiovascular homeostasis by controlling the vascular tone. Variations in sex hormones during the reproductive cycle of females affect the homeostasis of the cardiovascular system. Also, the evidence shows that estrogens show a cardioprotective effect. On this basis, this study describes some vascular responses induced by vasoactive substances during the estrous cycle in rats. We obtained the information available on this topic from the online databases that included scientific articles published in the Web of Science, PubMed, and Scielo. Many investigations have evaluated the vasoactive response of substances such as acetylcholine and norepinephrine during the estrous cycle. In this review, we specifically described the vascular response to vasoactive substances in rats during the estrous cycle, pregnancy, and in ovariectomized rats. In addition, we discussed the existence of different signaling pathways that modulate vascular function. The knowledge of these effects is relevant for the optimization and development of new treatments for some vascular pathologies.

Effects of two bisbenzylisoquinoline alkaloids, Antioquine and Tetrandrine, compared to Verapamil in Rat Thoracic Aorta.

The objective of this study was to compare two alkaloids (antioquine and tetrandrine) with verapamil; knowing that the smooth muscle respond to KCl and relationships with calcium. The effects of antioquine and tetrandrine, was studied in adults Wistar rat with modified methods used in the determination of aorta contractility and compared with verapamil effect in the same assays. The analysis of the effect of a drug or extract on aortic reactivity included maximal relaxation or maximal contraction (Cmax) (Phase 1). In our results, verapamil induced a blockade of 98.7 ± 0.7% (n = 6) in presence of endothelium and 97.9 ± 4.3% in ausence of endothelium, both in phase 1 and in phase 2 of 47.4 ± 4.1% (n = 6) in aortas in the presence of endothelium and 61.8 ± 1.1% in ausence of endothelium; Tetrandrine assays showed a phase 1 blocking effect of 63.4 ± 5.5 and 47.7 ± 2.9% (with and without endothelium, respectively) and phase 2 of 43.5 ± 6.2 and 28.5 ± 5.7%, (with and without endothelium, respectively). Antioquine presents in phase 1 and phase 2, a blockade that is not significant from the point of view of calcium antagonism. We can conclude that tetrandrine block the movement of calcium from both intracellular and extracellular deposits, with the greatest effect when aortas are in the presence of endothelium.

Antinociceptive antibiotics-loaded into solid lipid nanoparticles of prolonged release: Measuring pharmacological efficiency and time span on chronic monoarthritis rats.

Pain is a sensory experience of a complex physiological nature in which is not only involved the nervous system. Among its many features is the development of chronic pain that is more complicated to treat because of the central somatization processes involved, becoming inefficient treatments used in other forms of pain. Among them is the role of glial cells, whose participation is such that some authors have proposed to chronic pain as a gliopathy. Because of this, the drug target of possible treatments focuses on modulating nociceptive response affecting transduction into the central nervous system through affecting synapses in the dorsal horn of the spinal cord. Solid lipid nanoparticles enter the central nervous system, protecting the drug, and in addition to the advantage of having greater absorption surface, all factors that improve drug activity. This work is based on the development and characterization of lipid nanoparticles of solid phase incorporating two antibiotics, minocycline, and ciprofloxacin with antinociceptive properties and challenged them with a rat monoarthritis model using Sprague-Dawley adult male rats. The solid lipid nanoparticles were prepared to modify the lipid, and surfactant amounts to obtain the best encapsulation capacity of the antibiotics, size and z potential. By using the Randall-Selitto test, we measured its pharmacological efficiency as an anti-inflammatory and measuring the time span the antibiotics are active. The encapsulated antibiotics were at least 50% more efficient than the antibiotic alone, and that is possible to measure anti-inflammatory activity up to seven days after the antibiotic application. The former is important for example, in the veterinary field, since a single application of the antibiotic will be necessary for the complete treatment, avoiding excessive stress for the animals. We can conclude that antinociceptive antibiotics encapsulation is a very effective, environmentally safe and inexpensive method for improving the pharmacological efficiency and time span the antibiotics are acting. Since these antibiotics are both anti-microbial and antinociceptive, his use in the field of veterinary presents the advantage of being adequate in single doses, with the saving of time and stress to the animals under treatment.

Plantas medicinales de Panamá 2: etnobotánica de la Reserva Forestal La Tronosa, Provincia de Los Santos / Medicinal plants of Panamá 2: ethnobotanics of Forestal Reserve La Tronosa, Province of Los Santos

La Reserva Forestal La Tronosa se localiza en la provincia de Los Santos, distrito de Tonosí con una superficie de 20,579 ha. El objetivo de la investigación era determinar el uso de las plantas medicinales. La metodología incluye, caminatas etnobotánicas y la aplicación encuestas, en las comunidades: La Bijagual, Culebra, Corotúa y la Bonita. Se identificaron 108 especies y se procesaron 1,855 datos de procedencia y parte usada de las plantas, forma de preparación y propiedades curativas. La Bonita fue la comunidad que más usa las Plantas Medicinales en un 38%. La parte más usada de la planta fue la hoja (69 %) y se preparan en lavados (65%) e infusiones (57%). Las plantas más usadas son sábila, mastranto y salvia. Las enfermedades más comunes son: respiratorias (19,7 %), dolor de cuerpo (19%) y problemas estomacales (18%).

The Tronosa Forest Reserve is located in the province of Los Santos, Tonosí district with an area of 20.579 ha. The aim of the research was to determine the use of medicinal plants. The methodology includes surveys ethnobotanical walks and implementation in communities: La Bijagual, Culebra, Corotúa and La Bonita. Species were identified 108 and 1855 data source and used portion of the plants, the preparation form and processed healing properties. La Bonita was the community that uses the medicinal plants by 38%. The part of the plant used was the leaf (69%) and are prepared in wash (65%) and tea (57%). The plants most commonly used are aloe, mastranto and sage. The most common diseases are respiratory (19,7%), body pain (19%) and stomach problems (18%).

Plantas medicinales de Panamá 1: etnobotánica de la reserva forestal el montuoso / Medicinal plants of Panamá: ethnobotanics of the montuoso forestal reserve

Se investigó el uso de las plantas medicinales de las comunidades de la Reserva Forestal El Montuoso (RFM), en el Distrito de Las Minas Panamá, se incluyeron los asentamientos humanos de mayor densidad: Chepo, Caras Pintadas, Tres Puntas, La Loma del Montuoso y La Peña. Se identificaron 142 especies. De estas especies el 52 por ciento provienen de los bosques de esta reserva y 47 por ciento de los huertos familiares, no se ha observado por parte de la población, intenciones de domesticación de las plantas, provenientes del bosque para posteriormente sembrarlas en sus huertos familiares. La parte más usada de las plantas medicinales es la hoja que se consumen generalmente en infusiones; en tanto que las raíces y la corteza se cocinan por 5 a 20 minutos (decocción y reducción). El principal uso de las plantas medicinales en la RFM es para combatir problemas gastrointestinales, enfermedades asociados al resfriado común, dolores en el cuerpo, presión arterial alta y enfermedades dermatológicas. Entre las especies silvestres más usadas tenemos: hierba de pasmo (Siparuna guianensis Aubl, Siparuna pauciflora Perkins, Siparuna tonduziana Perkins) y la hierba de montaña (Piper darienense C.DC.). The cultivated species most used are: mastranto (Lippia alba (Mill.) N.E.Br.), lemongrass (Cymbopogon citratus (DC.) Stapf) y aloe (Aloe vera L.). Estas plantas medicinales representan un gran recurso para esta región de difícil acceso a los servicios de salud.

The use of medicinal plants in the communities of The Montuoso Forest Reserve (MFR), in the district of Las Minas Panama is investigated. Human settlements of higher density were also included: Chepo, Caras PIntadas, Tres Puntas, the Loma del Montuoso and La Peña. 142 species were identified. Of these species, 52 percent are coming from the forests of the reserve and 47 percent of home gardens. It has not been observed by the population, intentions of domestication of plants from the forest, then sow in their home gardens. The most widely used medicinal plants of the MFR are usually consumed in teas; while the roots and bark are cooked for 5-20 minutes (decoction and reduction). The main use of medicinal plants in the MFR is to treat gastrointestinal disorders, diseases associated with the common cold, body aches, high blood pressure and skin diseases. Among the wild species used are: Hierba de Pasmo (Siparuna guianensis Aubl, Siparuna pauciflora Perkins, Siparuna tonduziana Perkins) and mountain herb (Piper darienense C.DC.). The Most used cultivated species are: Mastranto (Lippia alba (Mill) N.E.Br.), Lemongrass (Cymbopogon citratus (DC) Stapf.) and Aloe (Aloe vera L). These medicinal plants are a great resource for this region of difficult access to health services.

Pseudoxandra sclerocarpa maas, colombian medicinal plant: a review / Pseudoxandra sclerocarpa maas, planta medicinal colombiana: una revisión

The Annonaceae family is one of the largest, with 130 genre and 2500 species, consisting of trees, shrubs and a few vines. Within this family, the Pseudoxandra genus of neotropical distribution is found. In Colombia, there are endemic and native species, distributed in the Amazon region and along the valley of the Magdalena River in the Chocó. Of the total of 22 species that form the genus in Colombia, Pseudoxandra sclerocarpa Maas is exclusive of the Antioquia region, receiving the common name of garrapato or frisolo. From this tree, bisbenzylisoquinolinic alkaloids like antioquine, medellline, obaberine, among others, has been isolated. Also neolignans: dieugenol and dehydro-1-O-methydehydrodieugenol. It is used in traditional medicine as an antiparasitic. From the pharmacological point of view, the alkaloids have shown activity against leishmaniasis and also have spasmolytic activity. Within the bisbenzylisoquinolinic alkaloids, antioquine has properties of being calcium antagonist.

La familia Annonaceae es uno de los más grandes, con 130 géneros y 2.500 especies, que consiste en árboles, arbustos y algunos bejucos. Dentro de esta familia, el género Pseudoxandra es de distribución neotropical. En Colombia existen especies endémicas y nativas, distribuidas en la región del Amazonas ya lo largo del valle del río Magdalena en el Chocó. Del total de 22 especies que forman el género en Colombia, Pseudoxandra sclerocarpa es exclusiva de la región de Antioquia, recibiendo el nombre común de garrapato o frisolo. De este árbol se ha aislado alcaloides bisbencilisoquinolínicos como antioquina, medelllina, obaberina, entre otros. También neolignanos: dieugenol y dehidro-1-O-metil-dehidrodieugenol. Se utiliza en la medicina tradicional como un antiparasitario. Desde el punto de vista farmacológico, los alcaloides han mostrado actividad contra la leishmaniasis y también tienen actividad espasmolítica. Dentro de los alcaloides bisbencilisoquinolínicos, antioquina tiene propiedades de ser antagonista del calcio.

ß2-adrenoceptor stimulation restores frontal cortex plasticity and improves visuospatial performance in hidden-prenatally-malnourished young-adult rats.

Moderate reduction in dietary protein composition of pregnant rats from 25% to 8% casein, calorically compensated by carbohydrates, has been described as a "hidden malnutrition" because it does not alter body and brain weights of pups at birth. However, this dietary treatment leads to altered central noradrenergic systems, impaired cortical long-term potentiation (LTP) and worsened visuo-spatial memory performance. Given the increasing interest on the role played by ß2-adrenoceptors (ß2-ARs) on brain plasticity, the present study aimed to address the following in hidden-malnourished and eutrophic control rats: (i) the expression levels of ß2-ARs in the frontal cortex determined by immunohistochemistry, and (ii) the effect of the ß2 selective agonist clenbuterol on both LTP elicited in vivo in the prefrontal cortex and visuospatial performance measured in an eight-arm radial maze. Our results showed that, prenatally malnourished rats exhibited a significant reduction of neocortical ß2-AR expression in adulthood. Concomitantly, they were unable to elicit and maintain prefrontal cortex LTP and exhibited lower visuospatial learning performance. Administration of clenbuterol (0.019, 0.038 and 0.075 mg/kg i.p.) enhanced LTP in malnourished and control animals and restored visuospatial learning performance in malnourished but not in normal rats, in a dose-dependent manner. The results suggest that decreased density of neocortical ß2-ARs during postnatal life, subsequent to hidden prenatal malnutrition might affect some synaptic networks required to elicit neocortical LTP and form visuospatial memory, since those neuroplastic deficits were counteracted by ß2-AR stimulation.

Pannexin 1: a novel participant in neuropathic pain signaling in the rat spinal cord.

Pannexin 1 (panx1) is a large-pore membrane channel expressed in many tissues of mammals, including neurons and glial cells. Panx1 channels are highly permeable to calcium and adenosine triphosphatase (ATP); on the other hand, they can be opened by ATP and glutamate, two crucial molecules for acute and chronic pain signaling in the spinal cord dorsal horn, thus suggesting that panx1 could be a key component for the generation of central sensitization during persistent pain. In this study, we examined the effect of three panx1 blockers, namely, 10panx peptide, carbenoxolone, and probenecid, on C-reflex wind-up activity and mechanical nociceptive behavior in a spared nerve injury neuropathic rat model involving sural nerve transection. In addition, the expression of panx1 protein in the dorsal horn of the ipsilateral lumbar spinal cord was measured in sural nerve-transected and sham-operated control rats. Sural nerve transection resulted in a lower threshold for C-reflex activation by electric stimulation of the injured hindpaw, together with persistent mechanical hypersensitivity to pressure stimuli applied to the paw. Intrathecal administration of the panx1 blockers significantly depressed the spinal C-reflex wind-up activity in both neuropathic and sham control rats, and decreased mechanical hyperalgesia in neuropathic rats without affecting the nociceptive threshold in sham animals. Western blotting showed that panx1 was similarly expressed in the dorsal horn of lumbar spinal cord from neuropathic and sham rats. The present results constitute the first evidence that panx1 channels play a significant role in the mechanisms underlying central sensitization in neuropathic pain.

Conocimiento etnobotanico tradicional y uso de plantas Medicinales en un area rural de la Región Metropolitana de Chile: estudio descriptivo / Traditional ethnobotanical knowledge and use of medicinal plants in a rural area of the metropolitan region of Chile: descriptive study

Con el fin de caracterizar y evaluar el conocimiento botánico perteneciente a la población en el área rural (poco abordado por la etnobotánica) se realizó un estudio a través de encuestas para aprender sobre plantas medicinales cultivadas y utilizadas en una zona rural de la Región Metropolitana (San Juan de Pirque). Las conclusiones son que los usuarios tienen un conocimiento híbrido (producto de los conocimientos tradicionales en combinación con la información de diversos tipos) de plantas medicinales. Hemos encontrado que la mayoría de las especies cultivadas en los jardines botánicos fueron especies introducidas y muy pocos las nativas. También, se les conocía por sus nombres comunes y no se detectaron nuevos nombres no descrito previamente en la literatura.

Electrophysiological Study of the Antinociception Produced by the Coapplication of (±)-CPP and Propentofylline in Monoarthritic Rats.

The NMDA receptor is central in the generation and maintenance of chronic pain. This receptor has several sites of modulation. One is the glutamate recognition site that can be blocked by (±)-3-(2-carboxypiperazin-yl)propyl-1-phosphoric acid or (±)-CPP. We investigated whether the effect of glial inhibition produced by propentophylline (PPF) can be enhanced when combined with (±)-CPP. We used Sprague-Dawley rats with experimental monoarthritis, administering intrathecally the ED30 for both drugs (3.97 µg of (±)-CPP and 1.42 µg of PPF), since this combination produces an antinociceptive supra-additive effect when used in mechanical nociception (Randall-Selitto test). The combination of (±)-PPF and CPP produced an antinociceptive effect which was greater than that each drug alone as tested by both the C reflex and windup. We conclude that the antinociceptive effect of the combination of (±)-PPF and CPP possibly generates a supra additive interaction type in monoarthritic rats.

Knockdown of α2C-adrenoceptors in the occipital cortex rescued long-term potentiation in hidden prenatally malnourished rats.

Moderate reduction in the protein content of the mother's diet calorically compensated by carbohydrates (the so-called "hidden" prenatal malnutrition) leads to increased neocortical expression of the α(2C)-adrenoceptor subtype, together with decreased cortical release of noradrenaline and impaired long-term potentiation (LTP) and visuospatial memory performance during the rat postnatal life. In order to study whether overexpression of the α(2C)-adrenoceptor subtype is causally related to the decreased indices of neocortical plasticity found in prenatally malnourished rats, we evaluated the effect of intracortical (occipital cortex) administration of an antisense oligodeoxynucleotide (ODN) raised against the α(2C)-adrenoceptor mRNA on the LTP elicited in vivo in the occipital cortex of hidden prenatally malnourished rats. In addition, we compare the effect of the antisense ODN to that produced by systemical administration of the subtype-nonselective α(2)-adrenoceptor antagonist atipamezole. Prenatal protein malnutrition led to impaired occipital cortex LTP together with increased expression of α(2C)-adrenoceptors (about twice Bmax) in the same cortical region. [(3)H]-rauwolscine binding assay showed that a 7-day intracortical antisense ODN treatment in the malnourished rats resulted in 50% knockdown of α(2C)-adrenoceptor expression and, in addition, completely rescued the ability of the occipital cortex to develop and maintain long-term potentiation. Atipamezole (0.3 mg/kg i.p.) also led to full recovery of neocortical LTP in malnourished rats. The present results argue in favor of our original hypothesis that the deleterious effect of prenatal malnutrition on neocortical plasticity in the adult progeny is in part consequence of increased neocortical α(2C)-adrenoceptor expression. This receptor subtype is known to be involved in the presynaptic control of noradrenaline release from central neurons, a neurotransmitter that critically influences LTP and memory formation.

Antinociceptive interaction of (±)-CPP and propentofylline in monoarthritic rats.

INTRODUCTION: Multiple studies have shown that glial cells of the spinal cord, such as astrocytes and microglia, have close contact with neurons, suggesting the term tripartite synapse. In these synapses, astrocytes surrounding neurons contribute to neuronal excitability and synaptic transmission, thereby increasing nociception and thus the persistence of chronic pain. Conversely, the N-methyl-D-aspartate (NMDA) receptor is crucial in the generation and maintenance of chronic pain. It has multiple sites of modulation. One is the site of recognition of extracellular neurotransmitter (glutamate), which can be blocked by competitive antagonists such as (3-(2-carboxipiperazin-4)1-propyl phosphonic acid), (±)-CPP, resulting in a blockade of the calcium current and thus the intracellular transduction process. In the present study, we investigated whether the potential antinociceptive effect of glial inhibition produced by propentofylline (PPF) can be enhanced when combined with an NMDA-receptor inhibitor such as (±)-CPP. METHODS: We used Sprague-Dawley monoarthritic rats. The monoarthritis was induced by injection of complete Freund adjuvant in the right tibiotarsal joint. Four weeks later, rats were treated with PPF (1, 10, 30, and 100 µg/10 µl) intrathecally (i.t.) for 10 days, injected once with (±)-CPP (2.5, 5, 12.5, 25, 50, and 100 µg/10 µl, i.t.), or both treatments combined. The antinociceptive effect was evaluated on day 11 for PPF and immediately to (±)-CPP, by assessing the vocalization threshold to mechanical stimulation of the arthritic paw. RESULTS: The data indicate that intrathecal administration of increasing concentrations of (±)-CPP or PPF produced a significant dose-dependent antinociceptive effect with respect to monoarthritic rats receiving saline. The linear regression analysis showed that the dose that produces 30% of maximal effect (ED30) for i.t. (±)-CPP was 3.97 µg, and 1.42 µg for i.t. PPF. The administration of the PPF and (±)-CPP combination in fixed proportions of ED30 produced a dose-dependent antinociceptive effect, showing an interaction of the supraadditive type. CONCLUSIONS: The results suggest that glia inhibitors can synergically potentiate the effect of glutamate blockers for the treatment of chronic inflammatory pain.

Antinociceptive effect of rat D-serine racemase inhibitors, L-serine-O-sulfate, and L-erythro-3-hydroxyaspartate in an arthritic pain model.

N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D-serine, synthesized from L-serine by a pyridoxal 5'-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L-serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 µg/10 µL) and LEHA (100 µg/10 µL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 µg/10 µL of D-serine were injected intrathecally. Since no in vivo results have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain.

Reflejo C evocado en el músculo digástrico: un nuevo método para evaluar actividad wind-up trigeminal aplicable a principios activos de plantas medicinales / C-reflex evoked in the digastric muscle: a new method for evaluating trigeminal wind-up activity applicable to active principles of medicinal plants

Wind-up is a measure of nociceptive neurons synaptic potentiation and constitutes an important mechanism in the generation of central sensitization in chronic pain. At the spinal level, the C-evoked reflex in the bicep femoris muscle, by low frequency repetitive stimulation of the sural nerve, has enabled us to evaluate the wind-up of nociceptive neurons of the dorsal horn, and also the effect of antinociceptive drugs with a possible potential therapeutic value in chronic pain. In the present work, we electrophysiologically evaluated the trigeminal wind-up activity, utilizing as an experimental paradigm the evoked C-reflex in the Sprague-Dawley rat digastric muscle. The results obtained indicate that: (a) It is possible to evoke an electromyographic reflex in the digastric muscle by stimulation of C-fibers belonging to the third trigeminal branch; (b) It is possible to potentiate the trigeminal C-reflex with low frequency stimuli (wind-up) and (c) it is possible to depress the trigeminal wind-up with the μ-opioid agonist morphine and with the NMDA receptor antagonist, ketamine. We can conclude that the simple measurement of the trigeminal wind-up will facilitate future studies on the analgesic efficacy of new drugs in oro-facial chronic pain syndromes like migraine and with special emphasis on medicinal plant active principles.

El wind-up refleja la potenciación sináptica en neuronas nociceptivas y constituye un importante mecanismo en la generación de sensibilización central en dolor crónico. A nivel espinal, el reflejo C evocado en el músculo bicep femoris por estimulación repetitiva de baja frecuencia del nervio sural ha permitido evaluar la actividad wind-up en neuronas nociceptivas del cuerno dorsal, así como el efecto de drogas antinociceptivas con un posible potencial terapéutico en dolor crónico. En el presente trabajo evaluamos electrofisiológicamente la actividad wind-up trigeminal, utilizando como paradigma experimental el reflejo C evocado en el músculo digástrico de ratas Sprague-Dawley. Los resultados obtenidos indican que: (a) es posible evocar un reflejo electromiográfico en el músculo digástrico de la rata por estimulación de fibras C de la tercera rama del trigémino; (b) es posible potenciar el reflejo C trigeminal con estímulos de baja frecuencia (wind-up) y (c) es posible deprimir el wind-up trigeminal con el agonista μ-opioide morfina y con el antagonista NMDA, ketamina. Podemos concluir que la medición simple del wind-up trigeminal mediante el reflejo C evocado en el músculo digástrico facilitará futuros estudios sobre eficacia analgésica de nuevos fármacos en cuadros de dolor orofacial crónicos, como la migraña, con especial énfasis en los principios activos de plantas medicinales.

Effect of modafinil on learning performance and neocortical long-term potentiation in rats.

Modafinil is a novel wake-promoting agent whose effects on cognitive performance have begun to be addressed at both preclinical and clinical level. The present study was designed to investigate in rats the effects of chronic modafinil administration on cognitive performance by evaluating: (i) working and reference memories in an Olton 4×4 maze, and (ii) learning of a complex operant conditioning task in a Skinner box. In addition, the effect of modafinil on the ability of the rat frontal cortex to develop long-term potentiation (LTP) was also studied. Chronic modafinil did not significantly modify working memory errors but decreased long-term memory errors on the Olton 4×4 maze, meaning that the drug may have a favourable profile on performance of visuo-spatial tasks (typically, a hippocampus-dependent task) when chronically administered. On the other hand, chronic modafinil resulted in a marked decrease of successful responses in a complex operant conditioning learning, which means that repeated administration of the drug influences negatively problem-solving abilities when confronting the rat to a sequencing task (typically, a prefrontal cortex-dependent task). In addition, in vivo electrophysiology showed that modafinil resulted in impaired capacity of the rat prefrontal cortex to develop LTP following tetanization. It is concluded that modafinil can improve the performance of spatial tasks that depend almost exclusively on hippocampal functioning, but not the performance in tasks including a temporal factor where the prefrontal cortex plays an important role. The fact that modafinil together with preventing operant conditioning learning was also able to block LTP induction in the prefrontal cortex, suggests that the drug could interfere some critical component required for LTP can be developed, thereby altering neuroplastic capabilities of the prefrontal cortex.

Effect of interleukin-1beta on spinal cord nociceptive transmission of normal and monoarthritic rats after disruption of glial function.

INTRODUCTION: Cytokines produced by spinal cord glia after peripheral injuries have a relevant role in the maintenance of pain states. Thus, while IL-1beta is overexpressed in the spinal cords of animals submitted to experimental arthritis and other chronic pain models, intrathecal administration of IL-1beta to healthy animals induces hyperalgesia and allodynia and enhances wind-up activity in dorsal horn neurons. METHODS: To investigate the functional contribution of glial cells in the spinal cord nociceptive transmission, the effect of intrathecally administered IL-1beta was studied in both normal and adjuvant-induced arthritic rats with or without glial inhibition. Four weeks after induction of monoarthritis, rats were treated with the glial cell inhibitor propentofylline (10 microg i.t. daily during 10 days) and submitted to a C-fiber-mediated reflex paradigm evoked by single and repetitive (wind-up) electric stimulation. RESULTS: Both the propentofylline treatment and the monoarthritic condition modified the stimulating current required for threshold activation of C reflex responses. Intrathecal IL-1beta increased spinal cord wind-up activity in normal and monoarthritic rats without propentofylline pre-treatment, but resulted in decreased wind-up activity in normal and monoarthritic propentofylline-treated animals. Intrathecal saline did not produce any effect. Thus, glial inactivation reverted into inhibition the excitatory effect of IL-1beta on spinal cord wind-up, irrespective of the normal or monoarthritic condition of rats. CONCLUSIONS: The results suggest that the excitatory effect of nanomolar doses of IL-1beta on spinal wind-up in healthy rats is produced by an unidentified glial mediator, while the inhibitory effects of IL-1beta on wind-up activity in animals with inactivated glia resulted from a direct effect of the cytokine on dorsal horn neurons. The present study failed to demonstrate a differential sensitivity of normal and monoarthritic rats to IL-1beta administration into the spinal cord and to disruption of beta glial function, as both normal and monoarthritic animals changes wind-up activity in the same direction after propentofylline treatment, suggesting that after glial inhibition normal and monoarthritic animals behave similarly relative to the capability of dorsal horn neurons to generate wind-up activity when repeatedly stimulated by C-fibers.

Effects of interleukin-1beta on spinal cord nociceptive transmission in intact and propentofylline-treated rats.

To investigate the contribution of glial cells in the spinal cord nociceptive transmission, the effect of intrathecally administered interleukin-1beta (IL-1beta) was studied in rats treated with the glial cell inactivator propentofylline and submitted to a C-fiber-mediated reflex paradigm evoked by single and repetitive (wind-up) electric stimulation. Intrathecal IL-1beta did not modify the C reflex integrated activity in either group of animals, while producing increased wind-up in intact and decreased wind-up in propentofylline pre-treated rats. Results suggest that the excitatory effect of IL-1beta on spinal wind-up activity in healthy rats is produced by a glial mediator, whereas the inhibitory effect resulted from a direct effect of the cytokine on dorsal horn neurons.

Biphasic effect of apomorphine on rat nociception and effect of dopamine D2 receptor antagonists.

Studies on the effect of dopaminergic agonists in behavioral measures of nociception have gathered numerous but rather conflicting data. We studied the effects of the D(1)/D(2) receptor agonist apomorphine, as well as the modulatory effects of (S)-(-)-sulpiride (selective D(2) receptor antagonist) and domperidone (peripheral D(2) receptor antagonist), on thermal, mechanical and chemical nociception on rats. Apomorphine induced a biphasic dose-response relationship, low doses producing hyperalgesia and high doses inducing antinociception. Tonic (chemical) pain was more sensitive to apomorphine than phasic (thermal and mechanical thresholds) pain. (S)-(-)-sulpiride, but not domperidone, fully antagonized the antinociceptive effect of apomorphine in all three measures of nociception, pointing to a participation of D(2) dopaminergic receptors for the antinociceptive action of apomorphine. Although spinal sites for dopaminergic ligands mechanistically may account for the effects observed, involvement of dopaminergic receptors of the forebrain could probably explain better the antinociceptive effects of apomorphine, especially in chemical tonic pain.