Histamine H-4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus
ABSTRACT Histamine is a potent mediator of itch in humans, yet histamine H(1) receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H(4) receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma.
The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated.
Histamine and a selective histamine H(4) receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H(4) receptor knockout mice or by pretreatment with the selective histamine H(4) receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H(4) receptor antagonist treatment or in histamine H(4) receptor knockout mice. In all cases, the inhibitory effect of histamine H(4) receptor antagonist was greater than those observed with histamine H(1) receptor antagonists. The histamine H(4) receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons.
These results demonstrate that the histamine H(4) receptor is involved in pruritic responses in mice to a greater extent than the histamine H(1) receptor.
Histamine H(4) receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H(1) receptor antagonists are not effective.
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ABSTRACT: Atopic dermatitis is a common skin disease affecting up to 10% of children and approximately 2% of adults. Atopic dermatitis exhibits four major symptoms, including intense itching, dry skin, redness and exudation. The "itch-scratch-itch" cycle is one of the major features in atopic dermatitis. The pathophysiology and neurobiology of pruritus is unclear. Currently there are no single and universally effective pharmacological antipruritic drugs for treatment of atopic dermatitis. Thus, controlling of itch is a very important unmet need in patients suffering from atopic dermatitis. This article will update progress during the past 10 years of research in the field of pruritus of atopic dermatitis, focusing on aspects of pruritogens (including inflammatory lipids, histamine, serotonin, proteinases, proteinase-activating receptors, neurotransmitters, neuropeptides, and opioid peptides), antipruritic therapies, and emerging new targets. Based on recent progress, researchers expect to identify exciting possibilities for improved treatments and to develop new antipruritic drugs acting through novel targets, such as histamine H4 receptor, gastrin-releasing peptide receptor, MrgprA3, thromboxane A2 receptor and the putative SPC receptor.Biomolecules and Therapeutics 07/2010; 18(3). DOI:10.4062/biomolther.2010.18.3.246 · 0.84 Impact Factor
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ABSTRACT: Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.British Journal of Pharmacology 04/2009; 157(1):24-33. DOI:10.1111/j.1476-5381.2009.00151.x · 4.99 Impact Factor
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ABSTRACT: Although the role of prostanoids in itch was actively studied a decade ago, interest in this area has waned in recent years. Andoh et al. (2007, this issue) demonstrate that the prostanoid thromboxane A2 elicits scratching through its TP receptor. Identification of new itch mediators and their respective receptors within the skin will undoubtedly be the focus of future drug development for this distressing symptom.Journal of Investigative Dermatology 09/2007; 127(8):1857-9. DOI:10.1038/sj.jid.5700818 · 6.37 Impact Factor