• Kunie Nakajima, Hideaki Obata, Nobuhisa Iriuchijima, and Shigeru Saito.
• Department of Anesthesiology, Gunma University Graduate School of Medicine, Gunma, Japan.
• Pain. 2012 May 1; 153 (5): 990-997.

AbstractAntidepressants are often used for the treatment of neuropathic pain. Clinical studies suggest that the efficacy of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) for neuropathic pain is greater than that of selective 5-HT reuptake inhibitors (SSRIs). In the present study, we determined the efficacy and mechanisms involved in the antihyperalgesic effects of milnacipran, an SNRI, compared with paroxetine, an SSRI, and maprotiline, a selective NA reuptake inhibitor, using a rat model of neuropathic pain. Male Sprague-Dawley rats underwent spinal nerve ligation (SNL), and the withdrawal threshold to paw pressure was measured. Intraperitoneal injection of milnacipran (3-30mg/kg) produced a dose-dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the α(2)-adrenoceptor antagonist idazoxan (30μg), but not by various 5-HT receptor antagonists. Paroxetine produced an antihyperalgesic effect only at the highest dose tested (10mg/kg). This effect was reversed by intrathecal injection of both idazoxan and ondansetron (30μg), a 5-HT3 receptor antagonist. Maprotiline produced an antihyperalgesic effect (10 and 30mg/kg), and the effect was reversed by intrathecal idazoxan. In microdialysis studies, NA and 5-HT concentrations in the spinal dorsal horn were increased after injection of either milnacipran or paroxetine, and only NA was increased after maprotiline. Furthermore, the NA content in the spinal cord of SNL rats was greater than that in normal animals. These findings suggest that an increase in NA in the spinal cord plays an important role in the antihyperalgesic effects of not only NA reuptake inhibitors but also SSRIs.Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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