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

5-羟色胺-去甲肾上腺素再摄取抑制剂治疗神经性疼痛的伤害感受机制

基本信息

批准号：
21791435
负责人：
NAKAJIMA Kunie
金额：
$ 2.58万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21791435/
关键词：
疼痛治療学下行性抑制系抗うつ薬 SNRI SSRI 神経障害性疼痛神経損傷

项目摘要

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.

抗抑郁药通常用于治疗神经性疼痛。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优于选择性5-HT再摄取抑制剂（SSRIs）。在本研究中，我们使用神经性疼痛大鼠模型，确定了米那普仑（一种 SNRI）与帕罗西汀（一种 SSRI）和马普替林（一种选择性 NA 再摄取抑制剂）的抗痛觉过敏作用的功效和机制。雄性Sprague-Dawley大鼠接受脊神经结扎（SNL），并测量爪压力的缩回阈值。腹腔注射米那普仑(3-30 mg/kg)产生剂量依赖性的抗痛觉过敏作用。鞘内注射α2-肾上腺素受体拮抗剂咪唑克生(30μg)可逆转该效应，但各种5-HT受体拮抗剂则不能逆转该效应。帕罗西汀仅在最高测试剂量（10mg/kg）时产生抗痛觉过敏作用。鞘内注射咪唑克生和昂丹司琼（30μg）（一种5-HT3受体拮抗剂）可以逆转这种作用。马普替林产生抗痛觉过敏作用(10和30mg/kg)，鞘内注射达唑克生可逆转该作用。在微透析研究中，注射米那普仑或帕罗西汀后，脊髓背角的 NA 和 5-HT 浓度增加，而注射马普替林后，仅 NA 增加。此外，SNL大鼠脊髓中的NA含量高于正常动物。这些发现表明，脊髓中 NA 的增加不仅在 NA 再摄取抑制剂而且在 SSRI 的抗痛觉过敏作用中发挥着重要作用。