Neuroimagen y neurobiología de la adicción:un estudio sobre los cambios funcionales cerebrales en personas adictas a las cocaína

Decenes Jornades de Foment de la Investigació de la FCHS (Any 2004-2005)El consumo crónica de cocaína produce una reducción de la dopamina en ciertas áreas cerebrales, provocando una alteración en este sistema. (Volkow y cols., 1999; Wu y cols., 1997). El objetivo de este trabajo es estudiar mediante Resonancia Magnética Funcional, los efectos que el consumo crónico de cocaína provoca sobre el procesamiento emocional. Los participantes (10 pacientes adictos a la cocaína y 10 personas no adictas) realizaron una tarea de procesamiento emocional en la que visualizaban fotografías con contenido emocional positivo, negativo y neutro (Adaptación española del International Affective Pictures System, IAPS, moltó y cols. 2001) como fondo en un tarea de discriminación de letras. Los resultados muestran una menor activación en el núcleo accumbens, giro cingulado anterior y cortex orbitofrontal en personas adictas a la cocaína en comparación al grupo control, ante la visión de imágenes positivas. Mientras que, se observa una menor activación del giro cingulado anterior en pacientes en comparación a los controles, para la visión de imágenes negativas. Estos resultados sugieren que la tarea del IAPS es una buena tarea para activar áreas específicas de recompensa (N.acc y giro orbitofrontal). Y que los pacientes presentan una disfunción en el sistema de recompensa, lugar donde actúa la cocaína tras su administración, liberando dopamina. Esto podría tener como consecuencia una menor sensibilidad de estas personas para los reforzadores naturales

Desarrollo de un algoritmo de solución directa para el cálculo de distribuciones óptimas de cultivos bajo riego deficitario controlado

La adecuada gestión de un recurso natural cada vez más escaso, como es el agua, implica maximizar la eficiencia en su uso. Desde el punto de vista de una explotación agraria, es de la máxima importancia encontrar la distribución óptima de cultivos que maximice el margen bruto obtenido con el agua de riego disponible. Actualmente, los métodos de optimización disponibles para resolver este problema no lineal, recurren a métodos de optimización heurísticos de propósito general mucho más lentos y menos eficientes de lo que sería un algoritmo de optimización de solución directa, donde se conocen los mecanismos involucrados y las sinergias existentes entre los cultivos para la obtención de la solución óptima del problema. El objetivo del presente trabajo es desarrollar un algoritmo de solución directa capaz de determinar la distribución óptima de cultivos que sea compatible con el modelo MOPECO (Modelo de Optimización Económica del agua de riego). La solución óptima se consigue con sólo uno o dos cultivos, pero esta solución no es la más adecuada desde el punto de vista agronómico (p.e. rotación de cultivos, PAC, etc.), por lo que ha sido necesario adaptar el algoritmo desarrollado para manejar este tipo de situaciones. Para una hipotética explotación de 100 ha, considerando 10 cultivos diferentes y 11 escenarios de volumen de agua total disponible, se han comparado los resultados del algoritmo desarrollado con las soluciones ofrecidas por el software de optimización LINGO y los algoritmos genéticos. El algoritmo desarrollado consigue márgenes brutos un 0,5% inferiores a los de LINGO, y un 1,1% mayores que los algoritmos genéticos, reduciendo el tiempo de cálculo entre 50-100 y 2000 veces, respectivamente

Evidence for a Role of Endocannabinoids, Astrocytes and p38 Phosphorylation in the Resolution of Postoperative Pain

An alarming portion of patients develop persistent or chronic pain following surgical procedures, but the mechanisms underlying the transition from acute to chronic pain states are not fully understood. In general, endocannabinoids (ECBs) inhibit nociceptive processing by stimulating cannabinoid receptors type 1 (CB(1)) and type 2 (CB(2)). We have previously shown that intrathecal administration of a CB(2) receptor agonist reverses both surgical incision-induced behavioral hypersensitivity and associated over-expression of spinal glial markers. We therefore hypothesized that endocannabinoid signaling promotes the resolution of acute postoperative pain by modulating pro-inflammatory signaling in spinal cord glial cells.To test this hypothesis, rats receiving paw incision surgery were used as a model of acute postoperative pain that spontaneously resolves. We first characterized the concentration of ECBs and localization of CB(1) and CB(2) receptors in the spinal cord following paw incision. We then administered concomitant CB(1) and CB(2) receptor antagonists/inverse agonists (AM281 and AM630, 1 mg x kg(-1) each, i.p.) during the acute phase of paw incision-induced mechanical allodynia and evaluated the expression of glial cell markers and phosphorylated p38 (a MAPK associated with inflammation) in the lumbar dorsal horn. Dual blockade of CB(1) and CB(2) receptor signaling prevented the resolution of postoperative allodynia and resulted in persistent over-expression of spinal Glial Fibrillary Acidic Protein (GFAP, an astrocytic marker) and phospho-p38 in astrocytes. We provide evidence for the functional significance of these astrocytic changes by demonstrating that intrathecal administration of propentofylline (50 microg, i.t.) attenuated both persistent behavioral hypersensitivity and over-expression of GFAP and phospho-p38 in antagonist-treated animals.Our results demonstrate that endocannabinoid signaling via CB(1) and CB(2) receptors is necessary for the resolution of paw incision-induced behavioral hypersensitivity and for the limitation of pro-inflammatory signaling in astrocytes following surgical insult. Our findings suggest that therapeutic strategies designed to enhance endocannabinoid signaling may prevent patients from developing persistent or chronic pain states following surgery

Mitogen-Activated Protein Kinase Phosphatase-3 (MKP-3) in the Surgical Wound is Necessary for the Resolution of Postoperative Pain in Mice

Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69±0.17 g baseline vs 0.13±0.08 g day 1), which resolved normally by postoperative day 12 (0.46±0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19±0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4±6 cells/0.1 mm2) than WT mice (8.7±1.2 cells/0.1 mm2) on postoperative day 1 (vs 5-6 cells/0.1 mm2 at baseline) that returned to baseline 12 days after surgery (10-12 cells/0.1 mm2). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5- and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7-12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2

Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice

Mitogen-activated protein kinase (MAPK) phosphatase-3 (MKP-3) and its substrates (extracellular signal-regulated kinase [ERK] and p38) play an important role in pathophysiological mechanisms of acute postoperative and chronic neuropathic pain in the spinal cord. This study aimed to understand the role of MKP-3 and its target MAPKs at the site of surgical incision in nociceptive behavior. Wild-type (WT) and MKP-3 knockout (KO) mice underwent unilateral plantar hind paw incision. Mechanical allodynia was assessed by using von Frey filaments. Peripheral ERK-1/2 and p38 phosphorylation were measured by Western blot. Cell infiltration was determined using hematoxylin and eosin histological staining. Peripheral phosphorylated ERK-1/2 (p-ERK-1/2) inhibition was performed in MKP-3 KO mice. In WT mice, mechanical hypersensitivity was observed on postoperative day 1 (0.69±0.17 g baseline vs 0.13±0.08 g day 1), which resolved normally by postoperative day 12 (0.46±0.08 g, N=6). In MKP-3 KO mice, this hypersensitivity persisted at least 12 days after surgery (0.19±0.06 g; N=6). KO mice displayed higher numbers of infiltrating cells (51.4±6 cells/0.1 mm(2)) than WT mice (8.7±1.2 cells/0.1 mm(2)) on postoperative day 1 (vs 5–6 cells/0.1 mm(2) at baseline) that returned to baseline 12 days after surgery (10–12 cells/0.1 mm(2)). In WT mice, peripheral p-p38 and p-ERK-1/2 expression increased (5- and 3-fold, respectively) on postoperative days 1 and 5, and returned to basal levels 7–12 days after surgery (N=3 per group). Peripheral p-p38 levels in MKP-3 KO mice followed a similar expression pattern as WT mice. Peripheral p-ERK-1/2 levels in MKP-3 KO mice remained elevated 12 days after surgery (2.5-fold, N=3 per group). Administration of PD98059 (MEK inhibitor, N=8, vehicle N=9) reduced p-ERK-1/2 expression in the incised tissue and blocked hypersensitivity in MKP-3 KO mice (N=6). The findings of this study suggest that MKP-3 is pivotal for normal resolution of acute postoperative allodynia, through the regulation of peripheral p-ERK-1/2

Arabidopsis HAP2/GCS1 is a gamete fusion protein homologous to somatic and viral fusogens

Cell–cell fusion is inherent to sexual reproduction. Loss of HAPLESS 2/GENERATIVE CELL SPECIFIC 1 (HAP2/GCS1) proteins results in gamete fusion failure in diverse organisms, but their exact role is unclear. In this study, we show that Arabidopsis thaliana HAP2/GCS1 is sufficient to promote mammalian cell–cell fusion. Hemifusion and complete fusion depend on HAP2/GCS1 presence in both fusing cells. Furthermore, expression of HAP2 on the surface of pseudotyped vesicular stomatitis virus results in homotypic virus–cell fusion. We demonstrate that the Caenorhabditis elegans Epithelial Fusion Failure 1 (EFF-1) somatic cell fusogen can replace HAP2/GCS1 in one of the fusing membranes, indicating that HAP2/GCS1 and EFF-1 share a similar fusion mechanism. Structural modeling of the HAP2/GCS1 protein family predicts that they are homologous to EFF-1 and viral class II fusion proteins (e.g., Zika virus). We name this superfamily Fusexins: fusion proteins essential for sexual reproduction and exoplasmic merger of plasma membranes. We suggest a common origin and evolution of sexual reproduction, enveloped virus entry into cells, and somatic cell fusion