Chemotherapy-induced neuropathy (CIN) is a common complication of cancer treatment. Although CIN is treated with antidepressants that act at serotonin (5-HT) reuptake, the mechanisms of serotoninergic modulation of nociceptive transmission during CIN remain unknown, namely as to the involvement of the rostroventromedial medulla (RVM) and the role of spinal 5-HT3 receptors (5-HT3R). Male Wistar rats were injected with the cytostatic paclitaxel or vehicle solution. One month after CIN induction, we first studied the activation of RVM neurons, and then the activation of the local serotoninergic neurons. Immunostaining of phosphorylated extracellular signal-regulated kinase (pERK) indicated increased activation in paclitaxel-injected animals. The double immunohistochemistry of pERK and tryptophan hydroxylase (TpH) showed higher expression of TpH and increased co-localization of TpH and pERK of paclitaxel-injected animals, indicating that CIN is associated with increased activation of serotoninergic RVM neurons. The 5-HT content at the spinal dorsal horn assessed by HPLC was higher in paclitaxel-injected animals. The immunohistochemical analysis of 5-HT also showed increased expression at the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The levels of 5-HT3R detected by immunohistochemistry were higher in the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The intrathecal administration of the 5-HT3R antagonist ondansetron reversed mechanical and cold hypersensitivity in the von Frey and cold plate tests, respectively. The results indicate that CIN is associated with increased recruitment of descending 5-HT-mediated modulation from the RVM which affects the spinal serotoninergic system and probably accounts for pain hypersensitivity due to the pronociceptive role of spinal 5-HT3R. K E Y W O R D S analgesia, antidepressants, cancer, serotonin | 1757 COSTA-PEREIRA ET Al.

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Chemotherapy-induced peripheral neuropathy (CIPN) is a problem during cancer treatment and for cancer survivors but the central mechanisms underlying CIPN remain understudied. This study aims to determine if CIPN is associated with alterations of noradrenergic modulation of nociceptive transmission at the spinal cord. CIPN was induced in male Wistar rats by paclitaxel injections. One month after CIPN induction, the behavioral effects of the administration of reboxetine (noradrenaline reuptake inhibitor), clonidine (agonist of α 2 -adrenoreceptors; α 2− AR) and atipamezole (antagonist of α 2− AR) were evaluated using the von Frey and cold plate tests. Furthermore, we measured the expression of the noradrenaline biosynthetic enzyme dopamineβ-hydroxylase (DBH) and of α 2− AR in the spinal dorsal horn. Reboxetine and clonidine reversed the behavioral signs of CIPN whereas the opposite occurred with atipamezole. In the 3 pharmacological approaches, a higher effect was detected in mechanical allodynia, the pain modality which is under descending noradrenergic control. DBH expression was increased at the spinal dorsal horn of paclitaxel-injected animals. The enhanced noradrenergic inhibition during CIPN may represent an adaptation of the descending noradrenergic pain control system to the increased arrival of peripheral nociceptive input. A potentiation of the α 2− AR mediated antinociception at the spinal cord may represent a therapeutic opportunity to face CIPN.