Abstract
Glycogen synthase kinase-3² (GSK-3²) is a multifunctional serine/threonine kinase found in all eukaryotes that was initially named for its ability to phosphorylate glycogen synthase, but it is now recognized as a key component of multiple signaling pathways. Extracellular stimuli inhibit GSK-3beta activity by different intracellular mechanisms (AKT, PKA, PKC), in opposition, certain tyrosine kinases like ZAK-1 and Fyn or intracellular calcium increase can activate GSK-3beta. The GSK-3 activity depends on a previous phosphorylation of its substrate by other kinases like PKC or PKA. Literature data, from other and our unpublished data, indicate that the GSK-3 controls nociception, modulating or participating in the glutamatergic transmission, either in the spine as peripherally; in this last case, probably through the inhibition of NMDA and AMPA receptors or their intracellular pathways. The participation of GSK-3 in the nociceptive effect of TNF-alpha and IL-1beta in the spine is also known. Moreover, in peripheral sites GSK-3 control the mechanical and thermal hyperalgesia induced by PKC activation, bradikinin and with less potency the hyperalgesia induced by PGE2, but not the one induced by adrenaline. GSK-3 beta could be considered as a new therapeutic target for acute and chronic painful conditions. For these reasons, this project aims to study the effect of the acute and chronic administration of GSK-3beta inhibitors against the activity of glutamatergic NMDA, AMPA and kainate receptors. We also aim to study the acute and chronic modulation exerted by GSK-3 on Ca2+ and Na+ channels activity and expression in neurons of the dorsal root ganglia. Furthermore, we propose to investigate a possible modulation exerted by GSK-3beta on the purinergic receptors in satellite cells of the dorsal root ganglia. Finally, we want to verify a possible regulation of the IP3 and ryanodine receptors by GSK-3beta in the dorsal root ganglia cells. We hope to uncover the physiological functions of GSK-3 beta in the control of pain, and characterize it as a new antinociceptive target for treating acute and chronic pain. (AU)
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