In vivo molecular signal transduction of peripheral mechanisms of pain.
In vivo molecular signal transduction of peripheral mechanisms of pain.
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疼痛外周机制的体内分子信号转导。
DOI：
10.1254/jjp.79.263
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
H. Ueda
中科院分区：
文献类型：
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作者：
H. Ueda
虽然我们已经获得了一些药理工具和缺乏与疼痛相关的特定基因的突变小鼠，但由于我们一直使用传统的伤害性测试范式，可能同时驱动多个内源性分子影响伤害性感受，因此疼痛产生机制的不同分子基础仍未完全阐明。在这里，我将介绍一种新的伤害性测试范式。在这项测试中，我们通过测量外周应用单一种类的伤害性分子引起的屈肌伤害性反应，重点研究了多模式C纤维。此外，我们通过鞘内注射受体的反义寡核苷酸来消除伤害性感觉，从而确定了药物对伤害性终末的作用部位。通过使用这种伤害性测试范式的实验，首次揭示了多模式C纤维的主要神经递质P物质通过激活GQ/11和磷脂酶C直接刺激伤害性终末，然后通过质膜结合的三磷酸肌醇受体进行钙内流，缓激肽和组胺这两种内源性代表性疼痛产生物质分享了这一机制。另一种独特的机制是通过GI偶联受体，如伤害素(孤儿FQ)或Kyotorphin(酪氨酸-精氨酸)的受体。后一种机制被发现是通过从伤害性感受器末端释放P物质来实现的。未来的研究，包括对这一范式的一些修改，也应该对神经病理性疼痛的研究以及对疼痛生理学的理解有临床上的帮助。
Although we have obtained a number of pharmacological tools and mutant mice lacking specific genes related to the pain, the distinct molecular basis of the pain-producing mechanism has remained to be fully clarified since we have been using conventional paradigms of the nociception test that may drive multiple endogenous molecules affecting nociception at the same time. Here, I will introduce a new paradigm of the nociception test. In this test, we focused on polymodal C-fibers by measuring nociceptive flexor responses induced by the peripheral application of a single species of nociceptive molecule. In addition, we identified the site of drug actions on nociceptor endings by the fact that the nociception was abolished by the intrathecal pretreatment with antisense oligodeoxynucleotide for receptors. Throughout experiments using this paradigm of the nociception test, it was firstly revealed that substance P, a major neurotransmitter of polymodal C-fibers, directly stimulates nociceptor endings through activation of Gq/11 and phospholipase C, followed by Ca2+ influx through plasma membrane-bound inositol trisphosphate receptors, and that bradykinin and histamine, both endogenous representative pain-producing substances, share this mechanism. Another unique mechanism is through Gi-coupled receptors such as receptors for nociceptin (orphanin FQ) or kyotorphin (tyrosine-arginine). The latter mechanism was found to be mediated through a substance P release from nociceptor endings. Future studies including some modifications of this paradigm should be also clinically useful for neuropathic pain research as well as understanding of pain physiology.