Antinociceptive Effects of the Serotonin and Noradrenaline Reuptake Inhibitors Milnacipran and Duloxetine on Vincristine-Induced Neuropathic Pain Model in Mice

Vincristine is an anticancer drug used to treat a variety of cancer types, but it frequently causes peripheral neuropathy. Neuropathic pain is often associated with the appearance of abnormal sensory signs, such as allodynia. Milnacipran and duloxetine, serotonin/noradrenaline reuptake inhibitors, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of vincristine-induced mechanical allodynia in mice by milnacipran and duloxetine. To induce peripheral neuropathy, vincristine was administered once per day (0.1？mg/kg, intraperitoneally (i.p.)) for 7 days. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In vincristine-treated mice, mechanical allodynia was observed on days 3–28 of vincristine administration. A single administration of milnacipran (40？mg/kg, i.p.) or duloxetine (20？mg/kg, i.p.) had no effect on vincristine-induced mechanical allodynia. However, repeated administration of milnacipran (20 or 40？mg/kg, once per day, i.p.) or duloxetine (5, 10, or 20？mg/kg, once per day, i.p.) for 7 days significantly reduced vincristine-induced mechanical allodynia. These results suggest that chronic vincristine administration induces mechanical allodynia, and that repeated milnacipran and duloxetine administration may be an effective approach for the treatment of neuropathic pain caused by vincristine treatment for cancer. 1. Introduction Peripheral neurotoxicity induced by antineoplastic drugs (vinca-alkaloids, taxanes, and platin-based compounds) is a clinically significant complication that can be dose limiting and can substantially diminish the quality of life. Vincristine is a chemotherapeutic agent that can be used in the treatment of many types of human cancer, including leukemias, lymphomas, and sarcomas [1, 2]. The antitumor action of vincristine is due to its binding to beta-tubulin, which leads to disorganization of the axonal microtubule cytoskeleton. However, peripheral neuropathy is a relatively common side effect of chemotherapeutic treatment with vincristine, sometimes greatly reducing patients’ quality of life and their ability to perform activities of daily living [3]. Antidepressants and anticonvulsants have suppressive effects on neuropathic pain [4, 5], and antidepressants are widely used for the treatment of neuropathic pain. Indeed, antidepressants, particularly tricyclic antidepressants (TCAs), are regarded as first-line drugs for the treatment of neuropathic pain [4]. Recently, newer antidepressants have become