Topical cholecystokinin depresses itch-associated scratching behavior in mice.

Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Journal of Investigative Dermatology (Impact Factor: 6.19). 02/2011; 131(4):956-61. DOI: 10.1038/jid.2010.413
Source: PubMed

ABSTRACT Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using 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 in ICR mouse KCs. 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 may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders.

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    ABSTRACT: Pruritus, the sensation of itch, which evokes reflex scratching behavior, has a diverse etiology. Because of its clinical significance, mechanisms of pruriception are an important topic. In the present work we describe and validate a paw motion detector (PMD) system. The system employs a small removable metal band placed on one hind paw that provides a signal indicative of paw movement through perturbation of an electromagnetic (EM) field. C57Bl/6 mice were fitted with a unilateral hind paw band and adapted to testing cylinders equipped with EM signal emission and detection. The following observations were made: (1) in mice, unilateral SQ injection of 48/80 into the dorsolateral aspect of the neck evoked periodic high frequency bursts of scratching at the injected site with the ipsilateral (banded) but not the contralateral (not banded) hind paw. (2) Cross correlation between PMD and human observer counts after SQ 48/80 using the specified computational algorithm revealed a highly significant correlation. (3) SQ histamine and 48/80 over a 1hour interval produced dose dependent scratching, which diphenhydramine dose dependently reversed. Chloroquine scratching displayed an inverse u-shaped dose response curve, which was insensitive to diphenhydramine. (4) SQ 48/80 at intervals over 28 days showed no change in the scratching response within the same cohort of mice. (5) Power analysis showed 40% changes in scratching activity could be detected at the p<0.05 level with groups of 4 mice. These observations indicate that the system described can efficiently define the actions and pharmacology of pruritogenic agents.
    Journal of neuroscience methods 08/2012; 211(1):1-10. · 2.30 Impact Factor

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