Effect of tapentadol on neurons in the locus coeruleus

Tapentadol is a novel centrally acting drug that combines mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), producing analgesic effects in various painful conditions. We investigated the acute effects of tapentadol in the locus coeruleus (LC), a central nucleus regulated by the noradrenergic and opioid systems that is critical in pain modulation. In single-unit extracellular recordings of LC neurons from anaesthetized male SpragueeDawley rats, tapentadol clearly inhibited the spontaneous electrophysiological activity of LC neurons in a dose-dependent manner (ED50 ¼ 0.8 mg/kg). This inhibitory effect was reversed by RX821002 (an alpha2-adrenoceptor antagonist) and naloxone (a mu-opioid receptor antagonist) by 96.7% and 28.2%, respectively. Pretreatment with RX821002, Nethoxycarbonyl- 2-ethoxy-1-2-dihydroquinoline (EEDQ, an irreversible alpha2-adrenoceptor antagonist) or naloxone shifted the tapentadol doseeeffect curve to the right (ED50 ¼ 2.2 mg/kg, 2.0 mg/kg and 2.1 mg/kg, respectively). Furthermore, tapentadol inhibited the LC response to mechanical stimulation of the hindpaw in a dose-dependent manner. In summary, we demonstrate that acute administration of tapentadol inhibits LC neurons in vivo, mainly due to the activation of alpha2-adrenoceptors. These data suggest that both the noradrenergic and opioid systems participate in the inhibitory effect of tapentadol on LC neurons, albeit to different extents, which may account for its potent analgesic effect and mild opioidergic side-effects.This study was supported by grants from Grünenthal GmbH (OT2010/075); “Fondo de Investigación Sanitaria” (PI10/01221 and PI12/00915); CIBERSAM (G18); Junta de Andalucía, Consejería de Innovación, Ciencia y Empresa (CTS-510, CTS-4303 and CTS-7748); Cátedra Externa del Dolor Grünenthal-Universidad de Cádiz; FP7-PEOPLE-2010-RG (268377); FPU (AP2007-02397) and FPI (2011-145) fellowship

Neurobiología de la adicción a las sustancias de abuso

Las drogas de abuso causan adicción, la cual se caracteriza por su consumo compulsivo y fuera de control. Durante la primera fase del consumo, tienen lugar en el cerebro diversos cambios neuroquímicos y moleculares, que llevan a la dependencia y a la adicción. Todas las drogas adictivas actúan a través de mecanismos neurofisiológicos comunes, principalmente basados en la activación anómala del sistema mesolímbico dopaminérgico. Aunque el cerebro del adicto trata de adaptarse a la acción de la droga, hay cambios permanentes a nivel celular y molecular que subyacen al proceso adictivo y a la aparición de síntomas de abstinencia tras el cese del consumo de la droga. Además, estos cambios neurales parece que participan en la aparición del ‘ansia de droga’ o craving tras la abstinencia, qué es un deseo en controlado de droga, principal causa de recaída y que a menudo se inicia por estímulos asociados a la droga

Neurobiología de la adicción a las sustancias de abuso

Las drogas de abuso causan adicción, la cual se caracteriza por su consumo compulsivo y fuera de control. Durante la primera fase del consumo, tienen lugar en el cerebro diversos cambios neuroquímicos y moleculares, que llevan a la dependencia y a la adicción. Todas las drogas adictivas actúan a través de mecanismos neurofisiológicos comunes, principalmente basados en la activación anómala del sistema mesolímbico dopaminérgico. Aunque el cerebro del adicto trata de adaptarse a la acción de la droga, hay cambios permanentes a nivel celular y molecular que subyacen al proceso adictivo y a la aparición de síntomas de abstinencia tras el cese del consumo de la droga. Además, estos cambios neurales parece que participan en la aparición del ‘ansia de droga’ o craving tras la abstinencia, qué es un deseo en controlado de droga, principal causa de recaída y que a menudo se inicia por estímulos asociados a la droga

Neurobiología de la adicción a las sustancias de abuso

Las drogas de abuso causan adicción, la cual se caracteriza por su consumo compulsivo y fuera de control. Durante la primera fase del consumo, tienen lugar en el cerebro diversos cambios neuroquímicos y moleculares, que llevan a la dependencia y a la adicción. Todas las drogas adictivas actúan a través de mecanismos neurofisiológicos comunes, principalmente basados en la activación anómala del sistema mesolímbico dopaminérgico. Aunque el cerebro del adicto trata de adaptarse a la acción de la droga, hay cambios permanentes a nivel celular y molecular que subyacen al proceso adictivo y a la aparición de síntomas de abstinencia tras el cese del consumo de la droga. Además, estos cambios neurales parece que participan en la aparición del ‘ansia de droga’ o craving tras la abstinencia, qué es un deseo en controlado de droga, principal causa de recaída y que a menudo se inicia por estímulos asociados a la droga

Síntesis y caracterización de materiales absorbentes interpenetrados a partir de polímeros sensibles al pH y temperaturas.

[Sin resumen

Synthesis and characterization of chitosan hydrogels cross-linked with dicarboxylic acids

Chitosan hydrogels cross-linked with dicarboxylic acids were prepared. Succinic, glutaric and adipic acid were used as cross-linking agents, the goal being to compare the effect of the length of the chain on the behavior of the material obtained. The swelling properties were studied at different pHs and temperatures, and it was discovered that these properties depend particularly on the pH of the environment. Creep-recovery and stress-relaxation studies were performed to determine mechanical properties and the chitosan/succinic acid hydrogels exhibited a completely viscous behavior. Thermal studies were carried out using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC results revealed that the materials obtained are completely amorphous. Acetaminophen was used as a positive control for the release kinetics studies. Upon fitting the results to a specific mathematical model, it was determined that the release process is controlled by diffusion and relaxation of the polymer network

Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors

Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8(+) T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors