title: Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy.
abstract: Painful vincristine (VCR) neuropathy is a frequent and dose-limiting problem in cancer treatment. Here, we investigated how pain behavior is modulated in mice lacking the serotonin transporter (5-HTT-/- mice) after inducing neuropathy by intraperitoneal injections of VCR. We used standard tests for evoked pain, high performance liquid chromatography to measure serotonin (5-HT), and immunohistochemistry of L4/5 dorsal root ganglia (DRG) to assess neuronal injury and inflammation. After injections of VCR, 5-HTT-/- mice did not develop hypersensitivity to heat, in contrast to their wildtype (wt) littermates (p<0.05). Also, 5-HTT-/- mice recovered faster from mechanical hypersensitivity than wt mice (p<0.05). 5-HT levels were lower in the peripheral and central nervous tissue of vehicle or VCR-treated 5-HTT-/- mice compared to wt mice. VCR-treated mice had higher numbers of injured neurons as identified by immunostaining for activating transcription factor 3, and more immunoreactive macrophages in the L4/5 DRG than vehicle-treated mice. There was no difference between genotypes. Thus the 5-HTT-/- genotype did not protect mice from VCR-induced neuronal injury and macrophage infiltration in the DRG. Our results suggest that the reduced peripheral 5-HT levels of 5-HTT-/- mice in VCR neuropathy underlie the lack of heat hyperalgesia. Conversely, attenuation of mechanical allodynia in 5-HTT-/- mice may indicate reduced 5-HT-mediated facilitation in the central nervous system.
authors.affiliation: Department of Neurology, University of Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany. Hansen_N@klinik.uni-wuerzburg.de
authors.forename: Niels
authors.initials: N
authors.lastname: Hansen
authors.forename: Nurcan
authors.initials: N
authors.lastname: Uçeyler
authors.forename: Florian
authors.initials: F
authors.lastname: Palm
authors.forename: Marek
authors.initials: M
authors.lastname: Zelenka
authors.forename: Lydia
authors.initials: L
authors.lastname: Biko
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001921:Brain / Q000378:metabolism; D005260:Female; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017288:Pain Threshold; D017933:Peripheral Nervous System / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics* / Q000523:psychology; D011930:Reaction Time; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D014110:Touch; D014750:Vincristine / Q000009:adverse effects*
chemical_list: D000970:Antineoplastic Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D014750:Vincristine