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

我们观察了5-HT受体拮抗剂对坐骨神经慢性收缩损伤所致的神经性疼痛大鼠模型机械痛觉过敏的影响。5-HT_<1A>受体拮抗剂NAN-190、5-HT_<1A/1B>受体拮抗剂(-)-pindolol和5-HT_<3/4>受体拮抗剂托品司琼对痛觉过敏后肢痛阈的影响程度与正常后肢不同。然而，5-HT_<2A>受体拮抗剂沙格雷酸盐和酮色林可显著提高痛觉过敏后肢的痛阈，而正常后肢则无此作用。为了分析细胞基因表达可能发生的变化，我们对大鼠背根神经节细胞进行了基因分析。在神经节细胞中，PCR和RT-PCR分别证实了5-HT_<2A>受体的DNA和mRNA的存在。然而，痛觉侧的mRNA与正常侧相比没有变化。此外，神经生长因子（NGF）局部应用于后肢诱导痛觉过敏，可被5-HT_<2A>受体拮抗剂选择性抑制。4-甲基cathechol （4-MC）是一种神经生长因子的诱导剂，局部应用于局部组织，可明显降低痛觉过敏和非痛觉过敏后肢的痛阈。这些结果提示NGF的释放可能参与神经性疼痛模型痛觉过敏的发病机制，尽管坐骨神经部分结扎的NGF释放机制与4-MC不同。

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.