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Information × Registration Number 0220U101349, 0115U003632 , R & D reports Title Development of new analgesics based inhibitors of calcium-permeable AMPA receptors Разработка новейших обезболивающих средств на основе ингибиторов кальций-проницаемых АМРА рецепторов popup.stage_title Head Voitenko Nana V., Доктор біологічних наук Registration Date 10-02-2020 Organization Bogomolets Institute of Physiology popup.description2  In this work, it was shown that the Freund's adjuvant (CFA), which induces chronic peripheral inflammation, causes a time-dependent increase in the phosphorylation of the GluR2 subunit by the Ser880 end of AMPA receptors (AMPARs) in dorsal horn (DR) neurons. This phosphorylation is accompanied by a decrease in GluR2 affinity for its synaptically bound proteins, internalization of synaptic GluR2 subunits, and an increase in calcium-conducting GluR2-deprived AMPARs in DR neurons in inflammatory pain. The phosphorylation of the GluR2 subunit and its internalization depends on the activation of protein kinase Ca (PKCα) in DR neurons. Blockade of spinal PKCα by intrathecal injection of a pharmacological celeritrin blocker leads to attenuation of CFA-induced increase in the number, single-channel conductance, and Ca2 + -permeability of synaptic AMPARs in DR neurons. It has been shown that CFA-induced peripheral inflammation also increases the number of extrasynaptic Ca2 + permeable AMPARs in tonic DR neurons. Also, in the course of this work it was shown that the recently developed activation-dependent blockers of Ca2 + -permeable AMPARs allow to block only hyperactivated AMPARs without affecting normal physiological processes in the spinal cord. Gene therapy (PKCα knockdown) also alleviates inflammatory pain when administered both before and after the induction of inflammation. The revealed therapeutic effects were accompanied by a decrease in the activity of Ca2 + -penetrating AMPARs at DR synapses. Our results provide a novel therapeutic approach in the treatment of chronic pain based on the interference with the molecular mechanisms of AMPARs trafficking in central pain pathways. Product Description popup.authors Ivanova Svitlana Yu. Bilan Pavlo V. Bagats'ka Olena V. Voitenko Nana V. Dromaretsʹkyy Andriy V. Duzhyi Dmytro Ye. Zabenʹko Yelyzaveta Yu. Pivneva Tatyana A. Palyvoda Ludmila G. Sheremet Eugene Yu. Yatsenko Vasylʹ P. popup.nrat_date 2020-04-02 Close