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Alleviative effects of 5-HT_<2A> receptor antagonists on the neuropathic pain

5-HT_<2A>受体拮抗剂对神经病理性疼痛的缓解作用

基本信息

批准号：
15500271
负责人：
NISHIO Hiroaki
金额：
$ 1.98万
依托单位：
Fukuyama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT_<1A> receptor antagonist, (-)-pindolol, a 5-HT_<1A/1B> receptor antagonist, and tropisetron, a 5-HT_<3/4> receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT_<2A> receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In order to analyze the possible changes in cellular gene expression, gene analysis of the dorsal-root ganglion cell of rat was performed. In the ganglion cell, presence of DNA and mRNA for 5-HT_<2A> receptor was demonstrated by PCR and RT-PCR assay, respectively. However, mRNA of the hyperalgesic side did not changed from that of the normal side. Furthermore, local application of nerve growth factor (NGF) to the hind limb induced hyperalgesia, which was selectively inhibited by 5-HT_<2A> receptor antagonists. The local application of 4-methylcathechol (4-MC), an inducer of NGF in local tissue, apparently reduced the pain threshold in the hyperalgesia and non-hyperalgesia hind limbs. These results imply that NGF release might be involved in the pathogenesis of hyperalgesia in the neuropathic pain model, though the NGF release mechanism for the partial ligation of sciatic nerve was distinct from that for 4-MC.

我们研究了5-HT受体拮抗剂对慢性坐骨神经压迫性损伤制备的神经病理性疼痛大鼠模型中观察到的机械性痛觉过敏的影响。5-HT<1A>_（1A/1B）受体拮抗剂NAN-190、（-）-吲哚洛尔和5-HT_（3/4）受体拮抗剂托烷司琼对痛敏后肢痛阈的影响程度与正常后肢不同。然而，5-HT_2受体拮抗剂沙格雷酯和酮色林<2A>能显著提高痛觉过敏后肢的痛阈，而对正常后肢无明显影响。为了分析细胞基因表达的可能变化，对大鼠背根神经节细胞进行了基因分析。在神经节细胞中，5-HT_2受体的DNA和mRNA的存在<2A>分别用PCR和RT-PCR检测。而痛觉过敏侧的mRNA与正常侧相比无明显变化。此外，后肢局部应用神经生长因子（NGF）可引起痛觉过敏，5-HT_2受体拮抗剂可选择性地抑制<2A>这种痛敏。局部应用神经生长因子（NGF）诱导剂4-甲基儿茶素（4-MC）可明显降低痛觉过敏和非痛觉过敏后肢的痛阈。这些结果表明，NGF的释放可能参与了神经病理性疼痛模型中的痛觉过敏的发病机制，虽然部分结扎坐骨神经的NGF释放机制不同于4-MC。