Maria Alejandra Hossen

How best to fight that nasty itch – from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches

While the enormous clinical and psychosocial importance of pruritus in many areas of medicine and the detrimental effects of chronic ‘itch’ on the quality of life of an affected individual are widely appreciated, the complexity of this sensation is still often grossly underestimated. The current Controversies feature highlights this complexity by portraying pruritus as a truly interdisciplinary problem at the crossroads of neurophysiology, neuroimmunology, neuropharmacology, protease research, internal medicine, and dermatology, which is combated most successfully if one keeps the multilayered nature of ‘itch’ in mind and adopts a holistic treatment approach – beyond the customary, frequently frustrane monotherapy with histamine receptor antagonists. In view of the often unsatisfactory, unidimensional, and altogether rather crude standard instruments for pruritus management that we still tend to use in clinical practice today, an interdisciplinary team of pruritus experts here critically examines recent progress in pruritus research that future itch management must take into consideration. Focusing on new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus, and discussing available neuropharmacological tools, specific research avenues are highlighted, whose pursuit promises to lead to novel, and hopefully more effective, forms of pruritus management.

Involvement of histamine H3 receptors in scratching behaviour in mast cell-deficient mice

Summary Background Although the roles of histamine H3 receptors have been studied in several tissues such as the brain, lung, spleen, colon and peripheral sensory nerve endings, the involvement of H3 receptors in skin responses particularly in relation to scratching behaviour are not well documented.

Inhibitory effects of propolis granular A. P. C on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice

We examined the effect of propolis granular A. P. C on lung tumorigenesis in female A/J mice. Lung tumors were induced by the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administered in drinking water for 7 weeks in mice maintained on an AIN-76A semi-synthetic diet. Propolis granular A. P. C (100 mg/kg body wt.) was administered orally daily for 6 days/week from 1 week before NNK administration and throughout the experiment. Sixteen weeks after the NNK treatment, the mice were killed and the number of surface lung tumors was measured. The number of lung tumors in mice treated with NNK alone for 7 weeks (9.4 mg/mouse) was significantly more than in that observed in control mice. Propolis granular A. P. C significantly decreased the number of lung tumors induced by NNK. These results indicate that propolis granular A. P. C is effective in suppressing NNK-induced lung tumorigenesis in mice.

Histamine H3 receptors regulate vascular permeability changes in the skin of mast cell-deficient mice

The participation of histamine H(3) receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H(3) antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/W(v)) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H(1) antagonists diphenhydramine and chlorpheniramine and the NK(1) antagonists, L-732,138 and L-733,060, were able to antagonize H(3) antagonist-induced skin vascular permeability. These results indicated that blockade of H(3) receptors by H(3) antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction.

The role of chemical mediators in eosinophil infiltration in allergic rhinitis in mice

The involvement of chemical mediators other than histamine in eosinophil infiltration in the nasal mucosa was studied using histamine H(1) receptor-deficient mice. Histamine H(1) receptor-deficient mice and wild-type controls were immunized with ovalbumin and consecutive topical antigen instillation was performed. Histological alterations and eosinophil infiltration into the nasal mucosa of mice were examined. Diffuse infiltration of inflammatory cells and edema after sensitization with antigen were observed in the nasal mucosa in both wild-type and histamine H(1) receptor-deficient mice. The number of eosinophils in the nasal mucosa in mice sensitized with antigen was significantly increased as compared with controls. The number of eosinophils in the nasal mucosa was significantly decreased by cetirizine and epinastine, ramatroban and zafirlukast in wild-type mice. Not only histamine but also thromboxane A(2) and leukotrienes play important roles in allergic rhinitis, especially in the late phase participating in nasal eosinophilia.

Evaluation of the effects of anti-pruritic drugs on scratch responses using histamine H1 receptor-deficient mice.

The effects of anti-pruritic drugs on scratching behavior associated with passive cutaneous anaphylaxis in histamine H(1) receptor-deficient and wild-type mice were studied. Passive sensitization with mouse monoclonal anti-dinitrophenyl-immunoglobulin E (IgE) resulted in an increase in the incidence of scratching behavior induced by intravenous injection of dinitrophenyl-ovalbumin in both wild-type and histamine H(1) receptor-deficient mice. The histamine H(1) receptor antagonist diphenhydramine inhibited scratching behavior induced by antigen in passively sensitized wild-type mice, whereas no effect was observed in histamine H(1) receptor-deficient mice. On the other hand, oxatomide inhibited scratching behavior in both mice, although the effect in wild-type mice was more potent than that in histamine H(1) receptor-deficient mice. Tranilast inhibited scratching behavior with the same potency in both mice. We concluded that the scratching behavior associated with passive cutaneous anaphylaxis involves not only histamine H(1) receptors but also other chemical mediators. Furthermore, the results of the present study indicated that oxatomide has an antagonistic effect on histamine H(1) receptors as well as anti-pruritic effect in vivo.

Effects of second-generation histamine H1 receptor antagonists on the active avoidance response in rats

1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second‐generation histamine H1 receptor antagonists.

Effect of topical application of Brazilian propolis on scratching behavior induced by compound 48/80 in mice.

Background and aim: We investigated the effect of topical application of Brazilian propolis on scratching behavior induced by compound 48/80 in mice. Results: Propolis inhibited compound 48/80-induced scratching behavior when applied immediately after treatment with propolis at a dose of 3 mg/site. Dibucaine 0.3 mg/site also significantly inhibited compound 48/80-induced scratching behavior immediately after application. On the other hand, propolis inhibited compound 48/80-induced scratching behavior even 15, 30 and 60 min after application; however, dibucaine showed no significant inhibition of compound 48/80-induced scratching behavior 15, 30 and 60 min after application. In addition, propolis had no effect on increased vascular permeability just after application, but the drug had a significant effect 15, 30 and 60 min after application. On the contrary, histamine-induced scratching behavior was inhibited significantly by propolis just after application. On the other hand, propolis significantly inhibited histamine release from rat mast cells induced by compound 48/80 at a concentration of more than 10 μg/ml. Conclusion: From these results, it can be concluded that inhibition of scratching behavior induced by topical application occurred by both its local anesthetic and systemic action through inhibition of histamine release.