Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on scratching behavior in mice
Introduction
Itching is an unpleasant cutaneous sensation that provokes the desire to scratch [1], and is the most common symptom of various skin diseases, such as dry skin, atopic dermatitis and contact dermatitis. In these diseases, scratching provoked by itching aggravates skin lesions and worsens dermatitis [2]. It has been assumed that the important mediators for causing itching are histamine, prostaglandins, tryptase, IL-2 and substance P [3], [4], [5], [6], [7]. On the other hand, it has become clear that nerve growth factor (NGF) stimulates the extension and function of sensory nerve C fibers. An increase in sensory nerve C fibers in the epidermis is partly responsible for intense itching sensations [8]. In spite of a number of these findings, the mechanisms of itching are not yet completely understood; therefore, it is important to detect substances that trigger itching, and to elucidate the mechanism of itching in skin disease.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known environmental pollutant that causes toxicity through the aryl hydrocarbon receptor (AhR) [9]. In humans, TCDD causes skin diseases with itching [10], [11]. Furthermore, Tauchi et al. [11] reported that transgenic mice expressing the constitutive active form of AhR in keratinocytes developed skin lesions with itching. It is well known that type 2 helper T (Th 2) cells are important for itching in inflamed skin, but TCDD suppresses the Th2-type immune reaction by impairing of T-cell functions [12], [13]; therefore, it seems that TCDD does not cause an itching sensation by Th2-type immune responses, and other mechanisms may be important.
In this study, we therefore investigated whether TCDD induces itching in hairless mice, which are highly sensitive to pruritogens and suitable for time-course studies due to their hairless skin [14]. To enhance the sensitivity of TCDD, distilled water or acetone/olive oil as a trivial external stimulation was used. Furthermore, we studied the effects of antipruritic drugs on scratching behavior in order to identify the characteristics of this itch model.
Section snippets
Animals
Six-week-old male hairless mice (Hos:HR-1) were obtained from Hoshino Experimental Animal Supply, Saitama, Japan. The animals were housed in an air-conditioned room with controlled temperature (24 ± 2 °C) and humidity (55 ± 15%). Food and water were provided ad libitum. Hairless mice are suitable for time course studies due to their hairless skin. In addition, we have reported that hairless mice are comparatively more sensitive to pruritogens, except for histamine, than Nc/Nga, ICR and ddY mice [14]
Effect of TCDD on scratching behavior in hairless mice
Fig. 1 shows the changes in scratching behavior induced by TCDD. The number of scratching behaviors was unchanged even at a dose of 1 ng/kg. TCDD in combination with the distilled water application (Fig. 2A) or acetone/olive oil application (Fig. 2B) significantly increased scratching behavior from day 36 with 1 ng/kg and on day 54 with 0.3 ng/kg. It was confirmed that an increase of scratching behavior was observed only at the application site of distilled water or acetone /olive oil.
Changes in NGF contents in the skin
We measured
Discussion
First, TCDD was orally administered every day for 54 days and scratching behavior was counted. It was found that 1 ng/kg TCDD had no significant effect on scratching behavior, so a dose of 3 ng/kg was administered, which caused enlargement of the liver and spleen, which was observed for 54 days (data not shown), and 1 ng/kg TCDD was therefore used as the maximum dose. On the other hand, it is well recognized that skin disease with itching occurs in humans and mice with a long-term high concentration
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