title: The α9α10 nicotinic receptor antagonist α-conotoxin RgIA prevents neuropathic pain induced by oxaliplatin treatment.
abstract: Oxaliplatin, a third-generation diaminocyclohexane platinum drug, is widely used alone or in combination with 5-fluorouracil and leucovorin to treat metastatic colorectal, ovarian, and pancreatic cancers. Oxaliplatin long-term treatment is associated with the development of a dose-limiting painful neuropathy that dramatically impairs the patient's quality of life and therapy possibility. To study novel strategies to treat oxaliplatin-induced neuropathy, we evaluated α-conotoxin RgIA, a peptide that potently blocks the α9α10 nicotinic acetylcholine receptor (nAChR) subtype in a rat model of oxaliplatin-dependent neurotoxicity (2.4mgkg(-1) oxaliplatin intraperitoneally daily for 21days). The administration of RgIA (2 and 10nmol injected intramuscularly once a day concomitantly with oxaliplatin treatment), reduced the oxaliplatin-dependent hypersensitivity to mechanical and thermal noxious and non-noxious stimuli. Moreover, morphological modifications of L4-L5 dorsal root ganglia were significantly prevented. In the spinal cord the numerical increase of astrocyte cell density present in oxaliplatin-treated rats is partially prevented by RgIA treatment. Nevertheless, the administration of the α-conotoxin is able per se to elicit a numerical increase and a morphological activation of microglia and astrocytes in specific brain areas.
authors.affiliation: Department of Experimental and Clinical Medicine, DMSC - Anatomy and Histology Section, University of Florence, Italy. Electronic address: lessandra.pacini@unifi.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pacini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Maresca
authors.affiliation: Department of Experimental and Clinical Medicine, DMSC - Anatomy and Histology Section, University of Florence, Italy.
authors.forename: Jacopo Juno Valerio
authors.initials: JJ
authors.lastname: Branca
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, USA; Department of Biology, Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020916:Conotoxins / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced* / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018733:Nicotinic Antagonists / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D020916:Conotoxins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D018733:Nicotinic Antagonists; D009944:Organoplatinum Compounds; C510079:conotoxin alpha-RgIA, Conus regius; D000077150:Oxaliplatin
keywords: CNS glial cells; Neuropathy; Oxaliplatin; RgIA; α9α10 nAChRs selective antagonist