title: Spinal administration of mGluR5 antagonist prevents the onset of bortezomib induced neuropathic pain in rat.
abstract: Peripheral neuropathy is a common adverse effect of bortezomib-based chemotherapy. In this study we have investigated the role played by subtype 5 of metabotropic receptors in bortezomib induced peripheral neuropathy. Rats were administered with bortezomib three times weekly at 0.20 mg/kg for a total of 4 weeks in presence or absence of mGluR5 antagonist MPEP. The animals were submitted to paw-pressure test and tail sensory nerve conduction measurement more times during the treatment and follow-up. Bortezomib treatment induced a progressively increasing hyperalgesia in rat which was accompanied by a significant reduction in sensory nerve conduction velocity (SNCV). MPEP prevented the emergence of bortezomib-induced pain and counteracted SNCV reduction when co-administered with bortezomib treatment. Spinal extracellular glutamate levels increased in rats treated with bortezomib. Bortezomib-induced onset of the hyperalgesia and SNCV decrease could be prevented by agents that promote the reuptake of glutamate maintaining spinal glutamate at basal level. Our data support the manipulation of the glutamatergic system through the mGluR5 receptor in bortezomib induced peripheral neuropathy. The use of antagonists at the mGluR5, initiated at the same time as bortezomib-chemotherapy, might reduce the number of patients who develop painful peripheral chemo-neuropathy.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Unit, University of Florence, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menicacci
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cerretani
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Italy. Electronic address: enrica.bianchi@unisi.it.
authors.forename: Enrica
authors.initials: E
authors.lastname: Bianchi
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001897:Boronic Acids; D000069286:Bortezomib; D002443:Ceftriaxone / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology; D011719:Pyrazines; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D001897:Boronic Acids; D002491:Central Nervous System Agents; D018691:Excitatory Amino Acid Antagonists; D011719:Pyrazines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018698:Glutamic Acid; D000069286:Bortezomib; D002443:Ceftriaxone; C121465:6-methyl-2-(phenylethynyl)pyridine
keywords: Bortezomib; Hyperalgesia; Metabotropic glutamate receptor; Neuropathy; glutamate reuptake