Vía de señalización del receptor apoptótico Fas en la adicción a opiáceos, La

Resumen

The aim of this PhD work was to investigate the interactions between opioids receptors and the signaling pathway of the Fas/FADD (Fas Associated-Death Domain) receptor, involved in the regulation of apoptosis and neuronal plasticity. The main results and conclusions are: 1) opiate addiction in rat brain is associated with a strong up-regulation of the pro-apoptotic Fas receptor and a moderate down-regulation of the anti-apoptotic Bcl-2 oncoprotein, without altering the content of caspases-8/3, suggesting that possible apoptotic signals engaged by Fas activation would be offset by decreased signal transduction through FADD and effector caspases-8/3; 2) the mi-opioid receptors appears to be associated with a tonic stimulation of monomeric Fas receptor, whereas the delta-opioid receptors tonically inhibits the basal density of trimeric Fas as well as that of FADD. This suggests posible homeostatic interactions between mi- and delta-opioid receptors in the control of Fas receptor machinery, being a major task of the delta-receptor to restrain the activation of Fas signalling; 3) the direct involvement of the two MAP kinases (sequential activation of MEK and ERK) in the in vivo regulation of FADD by the opiate; 4) opiate addiction in human brain is associated with a down-regulation of the inmunodensity of FADD in the prefrontal cortex (short-term and long-term abuse) without altering Fas receptor and effector caspases-8/3; 5) opiate addiction in human brain (long-term abuse) is associated with a normal regulation of the components of the cyclic AMP pathway components (AC I, PKA, CREB, pCREB) and with an important down-regulation of the MAPK (specially pMEK and pERK) pathway components in the prefrontal cortex, suggesting alterations in the neuronal plasticity in those human brains. In summary, the results of this PhD work demonstrated a clear participation of the complex Fas/FADD in opiate addiction, suggesting a new level of complexity in the signaling mediated through the activation of opioids receptors, probably mediating non-apoptotic effects related with neuronal plasticity. "