title: Spinal RyR2 pathway regulated by the RNA-binding protein HuD induces pain hypersensitivity in antiretroviral neuropathy.
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 demonstrated and RyR2 silencing prevented the ddC-induced neuropathic pain. A positive regulation of gene expression on CaMKIIα by HuD was also observed, but sequestration of CaMKIIα had no effect on ddC-induced allodynia. The present findings identify a spinal RyR2 pathway activated in response to ddC administration, involving the binding activity on RyR2 mRNA by HuD. We propose the modulation of the RyR2 pathway as a therapeutic perspective in the management of antiretroviral painful neuropathy.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: M D
authors.initials: MD
authors.lastname: Sanna
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Peroni
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Quattrone
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy. Electronic address: nicoletta.galeotti@unifi.it.
authors.forename: N
authors.initials: N
authors.lastname: Galeotti
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D001058:Apomorphine / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D000067779:ELAV-Like Protein 4; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009447:Neuroblastoma / Q000473:pathology; D010146:Pain / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D017288:Pain Threshold / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013116:Spinal Cord / Q000502:physiology*; D016047:Zalcitabine / Q000633:toxicity*
chemical_list: D018712:Analgesics, Non-Narcotic; D019380:Anti-HIV Agents; D002121:Calcium Channel Blockers; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498011:Elavl4 protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; D016047:Zalcitabine; D001058:Apomorphine
keywords: Antiretroviral; CaMKIIα; HuD; Neuropathy; RyR