Antisense knock down of TRPA1, but not TRPM8. alleviates cold hyperalgesia after spinal nerve ligation in rats
Antisense knock down of TRPA1, but not TRPM8. alleviates cold hyperalgesia after spinal nerve ligation in rats
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DOI：
10.1016/j.expneurol.2006.01.031
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发表时间：
2006-07-01
影响因子：
5.3
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
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作者：
Katsura, Hirokazu;Obata, Koichi;Noguchi, Koichi
神经性疼痛患者经常对冷刺激过敏。然而，这种对冷的敏感性增强的潜在机制还没有很好地理解。部分神经损伤后，在几种神经病理性疼痛模型中，完整的小背根神经节（DRG）神经元中的瞬时受体电位离子通道TRPV 1增加。在本研究中，我们精确地检查了L5脊神经结扎（SNL）后L4和L5 DRG中冷痛觉过敏的发生率和TRPA 1和TRPM 8表达的变化，因为这可能是两个不同的TRPA 1和TRPM 8表达小神经元群体的激活引起的冷感觉。我们首次证实L5 SNL大鼠在手术后出现冷痛觉过敏超过14天。在L5 SNL后第1 ~ 14天，邻近未损伤的L4 DRG中，小直径至中等直径的trkA阳性神经元TRPA 1 mRNA表达增加。这种上调与神经损伤诱导的后爪冷痛觉过敏的发展和维持相对应。相反，在整个2周的实验时间过程中，L4 DRG中TRPM 8 mRNA/蛋白的表达没有变化。另一方面，在受损的L5背根神经节中，TRPA 1和TRPM 8的表达在结扎后2周内均下降。此外，鞘内注射TRPA 1，而不是TRPM 8，反义寡核苷酸抑制L5 SNL诱导的冷痛觉过敏。我们的数据表明，增加TRPA 1在未受伤的初级传入神经元可能有助于夸张的反应，在神经病理性疼痛模型中观察到的冷。(c)2006年爱思唯尔公司All rights reserved.
Patients with neuropathic pain frequently experience hypersensitivity to cold stimulation. However, the underlying mechanisms of this enhanced sensitivity to cold are not well understood. After partial nerve injury, the transient receptor potential ion channel TRPV1 increases in the intact small dorsal root ganglion (DRG) neurons in several neuropathic pain models. In the present study, we precisely examined the incidence of cold hyperalgesia and the changes of TRPA1 and TRPM8 expression in the L4 and L5 DRG following L5 spinal nerve ligation (SNL), because it is likely that the activation of two distinct populations of TRPA1- and TRPM8-expressing small neurons underlie the sensation of cold. We first confirmed that L5 SNL rats developed cold hyperalgesia for more than 14 days after surgery. In the nearby uninjured L4 DRG, TRPA1 mRNA expression increased in trkA-expressing small-to-medium diameter neurons from the 1st to 14th day after the L5 SNL. This upregulation corresponded well with the development and maintenance of nerve injury-induced cold hyperalgesia of the hind paw. In contrast, there was no change in the expression of the TRPM8 mRNA/protein in the L4 DRG throughout the 2-week time course of the experiment. In the injured L5 DRG, on the other hand, both TRPA1 and TRPM8 expression decreased over 2 weeks after ligation. Furthermore, intrathecal administration of TRPA1, but not TRPM8, antisense oligodeoxynucleotide suppressed the L5 SNL-induced cold hyperalgesia. Our data suggest that increased TRPA1 in uninjured primary afferent neurons may contribute to the exaggerated response to cold observed in the neuropathic pain model. (c) 2006 Elsevier Inc. All rights reserved.