Nuevos aspectos en la regulación de receptores g en el sistema nervioso. Estudio comparativo del receptor u y cannabinoide cb1

Resumen

In the nervous system, G-protein-coupled mu-opioids receptors (MORs) drive the initial steps of both positive effects of opioids, antinociception, and their addictive effects, tolerance and dependence. A single acute dose of morphine induces a strong desensitization without promoting the phosphorylation and recycling of MORs. The administration of subsequent doses or continuous administration of morphine leads to the phosphorilation and internalization of MORs. On the other hand DAMGO induces a robust internalization and recycling of MORs and a lower level of tolerance. However when these opioids are used in demanding protocols, the agonists deplete the surface MORs before the novo synthesis can replenish the system, leading inevitably to desensitization. There are different mechanisms implicated in the MOR desensitization, we studied some of them and our results could resume as follow: - The sequestering of activated G¿ subunits by certain RGS proteins reduces the responses to the agonist in neurons. Morphine induces a long-term transfer of G¿ subunits that remains even when the drug effects have dissapeared. During the time-course of the effects of DAMGO, the G¿ subunits underwent a transient transfer to RGS proteins and later, the recycled MORs in the plama membrane recovered control over these G proteins and the response to DAMGO was resensitized. - Morphine but not DAMGO provokes a sustained activation of CaMKII. Morphine triggers a NMDA/CaMKII-mediated mechanism to desensitize the MORs in the plasma membrane and receptor phosphorylation/internalization disrupts this negative feedback regulation. In morphine-activated MORs the RGS14 protein prevents GRKs from phosphorylating those residues required for ß-arresting-mediated endocytosis. In RGS14 knockdown mice morphine promoted MOR internalization, low level of tolerance and failed to activate CaMKII. - Morphine induces the MAPK activation. The RGS14 protein acts as a MAPK scaffold facilitating the formation of a Ras-Rap/Raf/ERK multiprotein complex to promote sustained ERK activation near from the MOR. This cascade is implicated in the development of opioid tolerance and synaptic plasticity. - The morphine-activated MORs promote an increase in cytosolic free zinc. The NMDAR/nNOS cascade, activated via MORs, provide the free zinc ions required for inactive PKC¿ to bind to HINT/RGSZ2 complex at the C terminus of the receptor. When the DAG generated by the action of opioid-released Gß¿ dimmers on phospholipase ß reaches adequate levels, PKC¿ is activated and leaves the HINT1/RGSZ2 to phosphorylate their targets close to the MOR. This phosphorylation decreases the intensity of the signals evoked by morphine. In the brain, cannabinoids can produce analgesic tolerance that is nos associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. CB1Rs like MORS interact with the HINT1/RGSZ2 signaling module, and both receptors regulate Gz proteins. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonist and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs.