Koivisto Ari, Jalava Niina, Bratty Raymond, Pertovaara Antti
Research and Development, Orion Corporation Orion Pharma, POB 425 (Tengströminkatu 8), 20101 Turku, Finland.
Research and Development, Orion Corporation, Orion Pharma, POB 6792, Nottingham NG1 1AH, UK.
Pharmaceuticals (Basel). 2018 Nov 1;11(4):117. doi: 10.3390/ph11040117.
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment.
在此，我们回顾了评估瞬时受体电位锚蛋白1（TRPA1）——一种钙通透性非选择性阳离子通道——在各种疼痛状况中作用的文献。在神经系统中，TRPA1在伤害性初级感觉神经元、星形胶质细胞、少突胶质细胞和雪旺细胞的亚群中表达。在伤害性初级感觉神经元的外周终末，它参与潜在有害刺激的转导，而在其中枢终末，它参与伤害性传递的放大。TRPA1是各种病理生理疼痛状况中产生的大量化学性质各异的促伤害性激动剂的最终共同通路。因此，与许多其他针对单一伤害性信号通路的药物相比，使用TRPA1拮抗剂进行疼痛治疗有望成为一种更优的方法。在实验动物研究中，TRPA1的药理学或基因阻断已有效减轻了各种病理生理疼痛实验模型中的机械性和冷痛超敏反应，且副作用极小（若有）。外周作用的TRPA1拮抗剂可能最适合减轻原发性痛觉过敏（如炎症诱导的外周神经终末致敏），而中枢作用的TRPA1拮抗剂预计最适合减轻那些传递的中枢放大起作用的疼痛状况（如由各种类型外周损伤引起的继发性痛觉过敏和触觉异常性疼痛）。在周围性糖尿病神经病变的实验模型中，TRPA1的长期阻断延缓了伤害性神经末梢及其功能的丧失，因此有望提供一种改善病情的治疗方法。
