title: Oxaliplatin evokes P2X7-dependent glutamate release in the cerebral cortex: A pain mechanism mediated by Pannexin 1.
abstract: Anticancer therapy based on the repeated administration of oxaliplatin is limited by the development of a neuropathic syndrome difficult to treat. Oxaliplatin neurotoxicity is based on complex nervous mechanisms, the comprehension of the role of single neurotransmitters and the knowledge of the signal flow among cells is matter of importance to improve therapeutic chances. In a rat model of oxaliplatin-induced neuropathy, we report increased P2X7-evoked glutamate release from cerebrocortical synaptosomes. The release was abolished by the P2X7 receptor (P2X7R) antagonists Brilliant-Blue-G (BBG) and A-438079, and significantly reduced by Carbenoxolone and the Pannexin 1 (Panx1) selective inhibitors Erioglaucine and (10)Panx suggesting the recruitment of Panx1. Aimed to evaluate the significance of P2X7R-Panx1 system activation in pain generated by oxaliplatin, pharmacological modulators were spinally infused by intrathecal catheter in oxaliplatin-treated animals. BBG, Erioglaucine and (10)Panx reverted oxaliplatin-dependent pain. Finally, the influence of the P2X7R-Panx1 system blockade on oxaliplatin anticancer activity was evaluated on the human colon cancer cell line HT-29. Prevention of HT-29 apoptosis and mortality was dependent by kind and concentration of P2X7R antagonists. On the contrary, the inhibition of Panx1 did not alter oxaliplatin lethality in tumor cells. It is concluded that glutamate release dependent on P2X7R is increased in cerebrocortical nerve terminals from oxaliplatin-treated rats; the increase is mediated by functional recruitment of Panx1; P2X7R antagonists and Panx1 inhibitors revert oxaliplatin-induced neuropathic pain; Panx1 inhibitors do not alter the oxaliplatin-induced mortality of cancer cells HT-29. The inhibition of Panx1 channel is suggested as a new and safe pharmacological target.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health - Neurofarba, Pharmacology and Toxicology Section, University of Florence, Florence, Italy. Electronic address: lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Pharmacy, Pharmacology and Toxicology Section, University of Genova, Genova, Italy. Electronic address: marcoli@pharmatox.unige.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marcoli
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: Matteo
authors.initials: M
authors.lastname: Zanardelli
authors.affiliation: Department of Pharmacy, Pharmacology and Toxicology Section, University of Genova, Genova, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Maura
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 Pharmacy, Pharmacology and Toxicology Section, University of Genova, Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cervetto
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001557:Benzenesulfonates / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017630:Connexins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D000077150:Oxaliplatin; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012394:Rosaniline Dyes / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D000700:Analgesics; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D017630:Connexins; D009419:Nerve Tissue Proteins; D009944:Organoplatinum Compounds; C492764:PANX1 protein, human; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; D013777:Tetrazoles; C479936:pannexin 1, rat; D000077150:Oxaliplatin; D018698:Glutamic Acid; C006796:brilliant blue; C004692:coomassie Brilliant Blue; D002229:Carbenoxolone
keywords: Chemotherapy-induced neuropathy; Oxaliplatin; P2X7; Pannexin 1; Synaptosome