Spinal RyR2 pathway regulated by the RNA-binding protein HuD induces pain hypersensitivity in antiretroviral neuropathy

Experimental Neurology
M D SannaNicoletta Galeotti

Abstract

The antiretroviral toxic neuropathy, a distal sensory polyneuropathy associated with antiretroviral treatment, is a frequently occurring neurological complication during treatment of patients with AIDS and often leads to discontinuation of antiretroviral therapy. The mechanisms by which antiretroviral drugs contribute to the development of neuropathic pain are not known. Using drugs that reduce intracellular calcium ions (Ca(2+)), we investigated the hypothesis that altered cytosolic Ca(2+) concentration contributes to the 2',3'-dideoxycytidine (ddC)-evoked painful neuropathy. Administration of ddC induced mechanical and cold allodynia, which were abolished by intrathecal administration of TMB-8, a blocker of Ca(2+) release from intracellular stores, and by ryanodine, a RyR antagonist. Treatment with the IP3R antagonist heparin prevented mechanical allodynia with no effect on thermal response. To further clarify the pathway involved, we investigated the role of HuD, a RNA binding protein involved in neuronal function. HuD silencing reverted both mechanical and cold allodynia inducing, a phenotype comparable to that of ryanodine-exposed mice. HuD binding to the RyR2 mRNA, the most abundant RyR isoform in the spinal cord, was dem...Continue Reading

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Citations

Jan 24, 2017·Brain Research·Maria Domenica SannaNicoletta Galeotti
May 16, 2019·Wiley Interdisciplinary Reviews. RNA·June Bryan I de la PeñaZachary T Campbell
Apr 25, 2019·International Journal of Molecular Sciences·Cosmin Cătălin MustăciosuBeatrice Mihaela Radu
Oct 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Raiza R BonomoVirginie Mansuy-Aubert

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