The nociceptive mechanism of serotonin-noradrenaline reuptake inhibitor in neuropathic pain

抗抑郁药常用于神经性疼痛的治疗。临床研究表明，血清素（5-HT）和去甲肾上腺素（NA）再摄取抑制剂（SNRIs）治疗神经性疼痛的疗效大于选择性5-HT再摄取抑制剂（SSRIs）。在本研究中，我们利用神经性疼痛大鼠模型，确定了milnacpran（一种SNRI类药物）与paroxetine（一种SSRI类药物）和mapro替林（一种选择性NA再摄取抑制剂）的抗痛觉作用的疗效和机制。雄性Sprague-Dawley大鼠行脊髓神经结扎术（SNL），测定足部压力戒断阈值。腹腔注射米那西普兰（3 ~ 30mg /kg）具有剂量依赖性的抗痛觉作用。鞘内注射α2-肾上腺素能受体拮抗剂咪唑嗪（30 μg）可逆转这种效应，但各种5-HT受体拮抗剂不能逆转这种效应。帕罗西汀仅在测试的最高剂量（10mg/kg）下产生抗痛觉作用。鞘内注射咪唑赞和昂丹司琼（30μg）（一种5-HT3受体拮抗剂）可逆转这种作用。马普替林产生抗痛觉作用（10和30mg/kg），鞘内注射咪唑嗪可逆转该作用。在微透析研究中，注射米那西普兰或帕罗西汀后脊髓背角内NA和5-HT浓度均升高，而注射马普替林后仅NA升高。SNL大鼠脊髓内NA含量明显高于正常动物。这些发现表明，脊髓内NA的增加不仅在NA再摄取抑制剂的抗痛觉作用中起重要作用，而且在SSRIs的抗痛觉作用中也起重要作用。

Antidepressants 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 to 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(3-30 mg/kg)produced a dose-dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the α2-adrenoceptor antagonist, idazoxan(30 μg), 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.