Control of itch by topical application of cholecystokinin and its use for novel therapy

胆囊收缩素（CCK）是一种胃肠激素，也是中枢神经系统（CNS）的神经肽。CCK可能在中枢神经系统中起下调作用，表现为其抗阿片的特性。CCK在周围神经系统的存在也有报道。我们研究了各种CCKs对小鼠外周瘙痒的抑制作用。在ICR小鼠剪断的背部涂上CCK合成肽，并在同一部位皮下注射P物质（SP）。局部应用硫酸化CCK8（CCK8S）和CCK7（CCK7S）可显著降低sp致划伤的频率，而非硫酸化CCK8、CCK7和CCK6则无显著降低。真皮注射CCK8S也降低了抓痕频率，提示真皮细胞和表皮角质形成细胞都是CCKs的作用靶点。通过实时PCR， CCK2R mRNA在小鼠胎皮肤源性肥大细胞（FSMCs）和中度ICR小鼠角质形成细胞中高表达。CCK2R是两种CCK受体之一。CCK8S降低体外复合48/80促进的FSMCs脱粒，并伴有细胞内钙浓度的短暂升高。这些发现表明CCK主要通过肥大细胞发挥抗瘙痒作用，局部CCK可能在临床上对瘙痒性皮肤病有用。

Cholecystokinin(CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in central nervous system(CNS). CCK may be a downregulator in CNS as represented by its anti-opioid properties. The existence of CCK in peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on the peripheral pruritus in mice. ICR mice were painted with CCK synthetic peptides on the clipped back and injected intradermally with substance P(SP) on the same site. The frequency of SP-induced scratch was reduced significantly by topical application of sulfated CCK8(CCK8S) and CCK7(CCK7S), but not by non-sulfated CCK8, CCK7 or CCK6. Dermal injection of CCK8S also depressed the scratch frequency, suggesting that dermal cells as well as epidermal keratinocytes are the targets of CCKs. By real-time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells(FSMCs) and moderately ICR mouse keratinocytes. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK exerts an anti-pruritic effect mainly via mast cells, and topical CCK may be clinically useful for pruritic skin disorders.