title: Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve.
abstract: To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established "chronic" schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Quartu
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: V A
authors.initials: VA
authors.lastname: Carozzi
authors.affiliation: Department of Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, MD 21201, USA ; Program in Neuroscience, University of Maryland, Baltimore, MD, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Dorsey
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Serra
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Poddighe
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Picci
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Boi
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Melis
authors.affiliation: Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Del Fiacco
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Meregalli
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chiorazzi
authors.affiliation: Department of Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, MD 21201, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Renn
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Marmiroli
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001897:Boronic Acids / Q000009:adverse effects* / Q000494:pharmacology; D000069286:Bortezomib; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D059225:Nociception / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013373:Substance P / Q000096:biosynthesis*; D050916:TRPV Cation Channels / Q000096:biosynthesis*
chemical_list: D001897:Boronic Acids; D009419:Nerve Tissue Proteins; D011719:Pyrazines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D000069286:Bortezomib; D015740:Calcitonin Gene-Related Peptide