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

胆囊收缩素（Cholecystokinin，CCK）是一种胃肠激素，也是中枢神经系统的一种神经肽。CCK可能是CNS中的下调剂，如其抗阿片性质所示。外周神经系统也有CCK存在的报道。本实验观察了不同CCK对小鼠皮肤瘙痒的抑制作用。ICR小鼠背部涂CCK合成肽，同一部位皮内注射P物质（SP）。局部应用硫酸化CCK 8（CCK 8 S）和CCK 7（CCK 7S）可显著降低SP诱导的划痕频率，但非硫酸化CCK 8、CCK 7或CCK 6则无此作用。皮肤注射CCK 8 S也降低了抓挠频率，表明真皮细胞以及表皮角质形成细胞是CCK的靶点。实时荧光定量PCR检测结果显示，CCK 2受体mRNA在小鼠胚胎皮肤源性肥大细胞（FSMCs）和ICR小鼠角质形成细胞中高表达。CCK 8 S在体外降低化合物48/80促进的FSMCs脱颗粒，并使细胞内钙离子浓度瞬时升高。这些结果表明，CCK主要通过肥大细胞发挥抗过敏作用，局部CCK可能对过敏性皮肤病有临床意义。

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.