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受体拮抗剂对通过坐骨神经的慢性狭窄损伤制备的神经性疼痛大鼠模型中观察到的机械性痛觉过敏的作用。 Nan-190，5-HT_ <1A>受体拮抗剂，（ - ） - Pindolol，5-HT_ <1a/1b>受体拮抗剂，以及Tropisetron（5-HT_ <3/3/4>受体拮抗剂）并未影响高呈HINDBEN limb的疼痛阈值，而痛苦的HINDBEN limb to the Hyperalgesic HindB and for n forne for the Hind formb n and fornation fornation formb and n and forman n normun n normun n ander pranase formal n normal n normal limb。然而，肌酸酯和酮蛋白，5-HT_ <2A>受体拮抗剂，显着升高了痛觉过敏的后肢的疼痛阈值，但在正常的后肢中没有显着升高。为了分析细胞基因表达的可能变化，进行了大鼠背根神经节细胞的基因分析。在神经节细胞中，分别通过PCR和RT-PCR测定法证明了5-HT_ <2A>受体的DNA和mRNA。但是，高温侧的mRNA与正常侧的mRNA没有变化。此外，神经生长因子（NGF）局部应用在后肢诱导的痛觉过敏中，这被5-HT_ <2A>受体拮抗剂选择性抑制。 NGF的诱导剂4-甲基甲酚（4-MC）的局部应用显然降低了Hypergersia和非毛刺后肢的疼痛阈值。这些结果表明，NGF释放可能与神经性疼痛模型中的痛觉过敏有关，尽管坐骨神经部分连接的NGF释放机制与4-MC不同。