Different roles of capsaicin-sensitive and H1 histamine receptor-expressing sensory neurones in itch of mosquito allergy in mice.

Although mosquito allergy induces the release of histamine, the itch-related response, scratching, is not effectively suppressed by blockade of H1 histamine receptors. To address this question, we examined the effects of neonatal capsaicin treatment on allergic reactions and H1 histamine receptor-expressing sensory neurones in mice. Neonatal capsaicin treatment almost completely abolished allergy-associated scratching, without effects on plasma extravasation or increase in serum concentrations of immunoglobulins E and G1. An injection of edema contents from an animal exhibiting allergic reaction elicited scratching in naive animals, suggesting the production of pruritogen(s) by allergic reaction; this production was not suppressed by neonatal capsaicin treatment. This treatment markedly decreased the number of sensory neurones immunoreactive for TRPV1 capsaicin receptor, with little effect on sensory neurones immunoreactive for neurofilament 200, a marker of myelinated A-fibre neurones. In addition, there was a trend towards a reduction in numbers of sensory neurones immunoreactive for H1 histamine receptor. The results suggest that capsaicin-sensitive sensory neurones that lack H1 histamine receptors play a key role in signalling of allergic itch.

Different dorsal horn neurons responding to histamine and allergic itch stimuli.

We examined whether different itch signals converge on the same dorsal horn neurons in mice. Intradermal injections of histamine and SLIGRL-NH2 (protease-activated receptor-2 agonist) induced scratching in naive mice and so did mosquito allergen in sensitized mice. These stimuli induced Fos expression in cells in the superficial dorsal horn. Fos-positive cells were mainly distributed within the isolectin B4-labeled region (inner aspect of lamina II) after histamine injection. In contrast, they were in the region dorsal to the isolectin B4-labeled region after injections of SLIGRL-NH2 and mosquito allergen. These results suggest that allergic itch signal is mediated by primary afferents expressing protease-activated receptor-2 and the neurons receiving signals of protease-associated itch and allergy-associated itch are different from those of histamine-induced itch.

Effects of topical application of tacrolimus on acute itch-associated responses in mice.

Using mice, we examined whether the topical application of tacrolimus would produce an acute anti-pruritic effect. An itch-related response, scratching, was elicited by intradermal injections of mosquito allergen (10 microg/site) in sensitized mice and SLIGRL-NH2 (protease-activated receptor-2 agonist, 50 nmol/site), histamine (100 nmol/site), serotonin (100 nmol/site) and substance P (100 nmol/site) in naive ones. Topical application of 1%, but neither 0.1% nor 0.3%, tacrolimus to the skin 1 h before injection inhibited scratching induced by mosquito allergen and SLIGRL-NH2, without effects on scratching induced by histamine, serotonin, and substance P. Topical tacrolimus also inhibited licking induced by an intraplantar injection of capsaicin (0.1 microg/site). These results suggest that topical tacrolimus exerts acute inhibitory effects on allergic and protease-activated receptor-2-mediated itching. Though precise mechanisms remain unclear, the action on sensory neurons expressing protease-activated receptor-2 and transient receptor potential vanilloid-1 capsaicin receptor may be involved in the inhibitory effects of tacrolimus.

Possible involvement of 5-lipoxygenase metabolite in itch-associated response of mosquito allergy in mice.

This study investigated endogenous mediators involved in mosquito allergy-associated 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 microM) 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.