ABSTRACT-We investigated itch-associated responses (scratching) to mosquito bites and the role of histamine and mast cells in mosquito-induced itching in mice. Although the first bites of mosquito Aedes albopictus did not increase scratching, repeated bites increased scratching. The response was not diminished even after an interval of 2 months. Similarly, repeated intradermal (i.d.) injections of salivary gland extract (SGE) from Aedes albopictus increased scratching after SGE injection itself and mosquito bites. The scratching peaked within 10 min and almost subsided by 60 min. The opioid antagonist naloxone (1 mg / kg, s.c.) inhibited scratching following SGE injection. Although the non-sedative H 1-histamine-receptor antagonist terfenadine (30 mg/ kg, p.o.) significantly suppressed scratching induced by histamine (100 nmol /site, i.d.) in either naive or mosquito-sensitized mice, it did not affect mosquito-induced scratching in mosquitosensitized mice. Repeated injections of SGE increased scratching in mast cell-deficient (WBB6F1-W /W v ) mice as well as in normal (WBB6F1-+/ +) littermates. Repeated exposure to mosquito bites roughly doubled serum concentrations of total IgE and IgG1, but not IgG2a. Repeated injections of SGE markedly increased plasma extravasation induced by mosquito bites and such an increase was almost completely suppressed by terfenadine (30 mg/ kg, p.o.). The results show the presence of histamine-mediated and histamineindependent mechanisms in cutaneous itching and suggest that histamine probably released from mast cells does not play an important role in itching in immediate allergic reaction. Our murine model of mosquito itching may be useful for studying the mechanisms of immediate allergic itching.

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We examined whether azelastine would inhibit itch-associated responses of mice to mosquito allergy. Repeated injections of mosquito salivary gland extract increased scratching and sensory nerve activity. Azelastine inhibited the increased scratching and nerve activity, while terfenadine was without effects. Dexamethasone did not affect the increased scratching. Azelastine suppressed high K(+)-induced increase in intracellular free Ca(2+) in primary cultures of mouse sensory neurons. Direct inhibition by azelastine of sensory neurons may be at least involved in the anti-pruritic effect of azelastine. Histamine, substance P, and leukotriene B(4) may not play a key role in the itching of mosquito allergy.

Abstract. This study investigated endogenous mediators involved in mosquito allergyassociated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg / kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg / kg), and the glucocorticoid betamethasone 17-valerate (3 mg / kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B 4 antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D 4 antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester, the H 2 histamine-receptor antagonist cimetidine, the H 1 histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT 1/ 2 serotonin receptors. Zileuton (100 mg / kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 µM) did not affect high K + -induced increase in intracellular Ca 2+ concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B 4 and cysteinyl leukotrienes are involved in mosquito allergy-associated itching.Keywords: itch of mosquito allergy, 5-lipoxygense metabolite, zileuton, cutaneous nerve branch, dorsal root ganglion neuron

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