The involvement of the neurosteroid allopregnanolone in the antihyperalgesic effect of paroxetine in a rat model of neuropathic pain
The involvement of the neurosteroid allopregnanolone in the antihyperalgesic effect of paroxetine in a rat model of neuropathic pain
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DOI：
10.1097/wnr.0b013e32834da80d
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发表时间：
2011-12
期刊：
影响因子：
1.7
通讯作者：
T. Kawano;Tomohiro Soga;H. Chi;S. Eguchi;Fumimoto Yamazaki;M. Yokoyama
中科院分区：
文献类型：
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作者：
T. Kawano;Tomohiro Soga;H. Chi;S. Eguchi;Fumimoto Yamazaki;M. Yokoyama
帕罗西汀增加神经类固醇的水平，如别孕酮(AP)，通过对-氨基丁酸A型受体的正变构调节影响中枢神经系统的兴奋性。在此，我们研究了AP合成在帕罗西汀诱导的大鼠腰段脊神经结扎(SNL)神经病理性疼痛模型中的抗痛觉过敏作用。在SNL大鼠中，皮下注射帕罗西汀可剂量依赖性地降低痛觉过敏反应的可能性，并增加脊椎中的AP水平，但对脑或血清中的AP水平没有影响。同时使用AP合成酶的抑制剂非那雄胺，可减弱帕罗西汀引起的止痛作用以及帕罗西汀引起的脊髓AP水平的升高。鞘内注射外源性AP可模拟帕罗西汀对赋形剂治疗的SNL大鼠的镇痛作用，而对帕罗西汀治疗的SNL大鼠无额外的镇痛作用。我们的研究结果表明，帕罗西汀在大鼠神经病理性疼痛模型中的止痛作用是由AP介导的。这些结果还表明，以AP合成为靶点的药物疗法可能是治疗神经病理性疼痛的一种有前途的疗法。
Paroxetine increases the levels of neurosteroids, such as allopregnanolone (AP), that influence the excitability of the central nervous system by positive allosteric modulation of -aminobutyric acid type A receptors. Here, we investigated the role of AP synthesis on the paroxetine-induced antihyperalgesic effect in a rat model of neuropathic pain induced by lumbar spinal nerve ligation (SNL). Subcutaneous administration of paroxetine in SNL rats, dose-dependently decreased the probability of hyperalgesic response and increased AP levels in the spine but not in either brain or serum. Concomitant treatment with an inhibitor of the AP-synthesizing enzyme, finasteride, attenuated the paroxetine-induced antihyperalgesic effect as well as the paroxetine-induced increase in spinal AP levels. Intrathecal injection of exogenous AP mimicked the analgesic effects of paroxetine in vehicle-treated SNL rats, whereas no additional analgesic effects were observed in paroxetine-treated SNL rats. Our findings suggest that the antihyperalgesic effect of paroxetine in a rat neuropathic pain model is AP-mediated. These results also suggest that pharmacological-based therapies targeting AP synthesis might be a promising treatment for neuropathic pain.