The α9α10 nicotinic receptor antagonist α-conotoxin RgIA prevents neuropathic pain induced by oxaliplatin treatment

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 a-conotoxin RgIA, a peptide that potently blocks the alpha 9 alpha 10 nicotinic acetylcholine receptor (nAChR) subtype in a rat model of oxaliplatin-dependent neurotoxicity (2A mg kg(-1) oxaliplatin intraperitoneally daily for 21 days). The administration of RgIA (2 and 10 nmol 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 alpha-conotoxin is able per se to elicit a numerical increase and a morphological activation of microglia and astrocytes in specific brain areas. (C) 2016 Elsevier Inc. All rights reserved.