Tominaga Mitsutoshi, Takamori Kenji
Itch (or pruritus) has been defined as an unpleasant sensation that provokes the desire to scratch. Itch is also believed to signal danger from various environmental factors or physiological abnormalities. Therefore, it frequently accompanies a variety of inflammatory skin conditions and systemic diseases. Histamine is the best-known pruritogen in humans and also acts as an experimental itch-causing substance. Clinically, antihistamines, i.e., histamine H-receptor blockers, are commonly used to treat all types of itching resulting from renal and liver diseases, as well as from serious skin diseases such as atopic dermatitis. However, antihistamines often lack efficacy in patients with chronic itch that may involve other agonists, including proteases, neuropeptides, cytokines, and opioids, and their cognate receptors, such as thermoreceptors, PARs, Mrgprs, and opioid receptors. Such pruritogenic mediators and modulators released in the periphery may directly activate itch-sensitive fibers, especially C-fibers, by binding to specific receptors on the nerve terminals (Ikoma et al. 2006; Paus et al. 2006; Xiao and Patapoutian 2011). Nerve fibers are also activated by exogenous mechanical, chemical, and biological stimuli, resulting in itch responses (Akiyama et al. 2010; Tominaga and Takamori 2010). Histological analyses have shown that epidermal nerve densities are increased in patients with atopic dermatitis and xerosis, suggesting that the higher density is partly responsible for itch sensitization in the periphery. Such hyperinnervation is probably caused by an imbalance of nerve elongation factors, such as nerve growth factor (NGF), and nerve repulsion factors, such as semaphorin 3A (Sema3A), produced by keratinocytes (Tominaga and Takamori 2010). These axonal guidance molecules may also act on keratinocytes, immune cells and vascular endothelial cells, and be indirectly involved in the modulation of itching. This chapter presents recent knowledge regarding itch sensitization associated with epidermal nerve density controlled by NGF and Sema3A, especially in atopic dermatitis.
瘙痒（或称作痒）被定义为一种引起搔抓欲望的不适感。瘙痒也被认为是各种环境因素或生理异常发出的危险信号。因此，它常常伴随着各种炎症性皮肤病和全身性疾病。组胺是人类最知名的致痒原，也是一种实验性致痒物质。临床上，抗组胺药，即组胺H受体阻滞剂，通常用于治疗由肾脏和肝脏疾病以及特应性皮炎等严重皮肤病引起的各类瘙痒。然而，抗组胺药对慢性瘙痒患者往往缺乏疗效，慢性瘙痒可能涉及其他激动剂，包括蛋白酶、神经肽、细胞因子和阿片类物质，以及它们的同源受体，如温度感受器、蛋白酶激活受体（PARs）、Mas相关G蛋白偶联受体（Mrgprs）和阿片受体。在外周释放的此类致痒介质和调节剂可能通过与神经末梢上的特定受体结合，直接激活瘙痒敏感纤维，尤其是C纤维（今田等，2006年；保斯等，2006年；肖和帕塔普蒂安，2011年）。神经纤维也会被外源性机械、化学和生物刺激激活，从而引发瘙痒反应（秋山等，2010年；富永和平森，2010年）。组织学分析表明，特应性皮炎和皮肤干燥症患者的表皮神经密度增加，这表明较高的神经密度在一定程度上导致了外周瘙痒致敏。这种神经纤维过度支配可能是由角质形成细胞产生的神经伸长因子（如神经生长因子，NGF）和神经排斥因子（如3A类信号素，Sema3A）失衡所致（富永和平森，2010年）。这些轴突导向分子也可能作用于角质形成细胞、免疫细胞和血管内皮细胞，并间接参与瘙痒的调节。本章介绍了关于由NGF和Sema3A控制的与表皮神经密度相关的瘙痒致敏的最新知识，并特别提及特应性皮炎。
